Myeloid derived suppressor cells (MDSC) are immune cells that dampen immune responses. In patients with cancer, MDSC are associated with adverse oncologic outcomes and therapeutic resistance. Pre-clinical evidence suggests that MDSC suppress anti-tumor immune responses. In this report, the biologic functions of MDSC are defined and evidence linking MDSC with the response to cancer immunotherapies in solid tumors are reviewed. Associations of MDSC in clinical bladder cancer cohorts are outlined in addition to evaluation of the suggested roles of MDSC in pre-clinical bladder cancer models. Human clinical trials that investigate possible MDSC modulators are highlighted, and therapeutic strategies to leverage MDSC biology in bladder cancer immunotherapy are outlined.
Developing effective systemic therapy for bladder cancer continues to present a challenge to oncology physicians and researchers. Cisplatin-based chemotherapy has been the best option for decades, but only 50% of patients benefit in the form of objective responses, and just 13–25% experience a complete response . For those who are ineligible for cisplatin-based regimens or experience progression of disease, in 2016–2017 the United States Food and Drug Administration approved five monoclonal antibodies that achieve immune checkpoint blockade by targeting the programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1) pathway. Immune checkpoint blockade can lead to durable complete responses for some patients, but overall objective response rates are only 15–31% [2–4].
An immune cell in the tumor microenvironment that may be important for inhibiting the immune response against bladder cancer is the myeloid derived suppressor cell (MDSC). This review summarizes what is currently known about MDSC function, known roles of MDSC in cancer, and how MDSC have been implicated in bladder cancer prognosis and in the context of different bladder cancer therapies. Completed and ongoing clinical trials that have evaluated potential MDSC-modifying therapeutics are highlighted. Finally, knowledge gaps and areas for advancement in the study of MDSC to enhance bladder cancer immunotherapy are presented.
OVERVIEW OF MDSC FUNCTION
Myeloid derived suppressor cells (MDSC) dampen immune responses. From a physiological standpoint, MDSC can be thought of as effectors of a homeostatic mechanism that regulate T cell-mediated inflammatory responses to pathogens . In mice, MDSC can be identified by species-specific cell surface markers (CD11b+Gr-1+) and may be further classified as monocytic (M-MDSC, Ly-6Chi) or granulocytic (G-MDSC, Ly-6G+) based on additional cell surface markers . MDSC are derived from monocyte, macrophage and dendritic cell progenitors (M-MDSC); or neutrophil, eosinophil, basophil and mast cell progenitors (G-MDSC) [5, 7]. G-MDSC are also referred to as polymorphonuclear (PMN)-MDSC, which differ from conventional neutrophils via expression of lectin-type oxidized LDL receptor 1 (LOX-1), which inhibits T cell proliferation [7, 8]. Intratumoral M-MDSC appear to differentiate into immune suppressive tumor associated macrophages (TAM) in response to tumor-hypoxia mediated STAT3 signaling . In humans, MDSC can be identified with different cell surface markers: CD33+ or CD11b+, HLA–DRlow and (LIN)–. (LIN– refers to cells negative for lineage markers CD3, CD19, CD56 and CD13) . Additionally, human M-MDSC are CD14+CD15– with stronger CD33 positivity than PMN-MDSC; PMN-MDSC are also CD66b+/CD14–/dimCD15+ with dim CD33 expression .
MDSC are triggered by chronic inflammatory stimuli such as chronic infection or malignancy,  which is why circulating MDSC are often found to be elevated in patients with a variety of cancer types. MDSC act in multiple ways to suppress T cell function. They are capable of producing reactive oxygen species (ROS), arginase-1, nitric oxide (NO), prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), inhibitory cytokines such as IL-10 and TGFβ, [5, 12] and inhibiting the ability of T cells to respond normally to IFNα- and IFNγ–mediated stimulation .
ROLE OF MDSC IN BENIGN CONDITIONS
Immunosuppression mediated by MDSC has been found to be important to physiological processes and benign conditions. For example, MDSC have been suggested to play an important role during human pregnancy. PMN-MDSC capable of suppressing T cell proliferation are elevated in the peripheral blood of pregnant women, suggesting a role in maternal-fetal tolerance . In addition, MDSC derived from human placenta have also been shown to be capable of polarizing CD4+ T cells toward a Th2 cytokine response, which is thought to promote maternal tolerance . MDSC may also be elevated near the end of life . Verschoor et al. found significantly higher levels of circulating CD11b+CD15+ PMN-MDSC in in a cohort of frail elderly individuals, as compared to younger adults .
Obesity has been characterized as a pro-inflammatory state,  and pre-clinical evidence implicates obesity as a stimulus for MDSC generation. Clements et al. using the BALB/c and C57BL/6 murine models, discovered that mice fed a high fat diet had substantial elevations in Gr-1+CD11b+ MDSC, and that fatty diet induced MDSC were also required for somatic fat accumulation .
MDSC are also likely to play important functions in the biology of autoimmune disease, organ transplant tolerance and immunodeficiencies. For example, Crook et al. studying a murine model of rheumatoid arthritis, found that adoptive transfer of MDSC from subjects with moderate arthritis could improve the condition of mice prone to severe arthritis . Meng et al. analyzed a cohort of patients with T cell mediated renal transplant rejection, and found that higher levels of circulating CD33+HLA-DR– MDSC were strongly associated with increased graft function, which is consistent with the function of MDSC to suppress effector T cell function . Murine studies have suggested that the ability of MDSC to delay allograft rejection depends on deficient Smad3 signaling (which is part of the TGFβ pathway) . Patients with primary or secondary inflammatory disorders such as common variable immunodeficiency  and early Alzheimer’s disease  have also been found to have elevated circulating MDSC.
The study of MDSC has several practical challenges . Immunohistochemistry markers to identify human MDSC in formalin fixed paraffin embedded tissues are lacking. Though their surface ligand-based classification is well-defined, the gating of HLA-DRlow/neg populations during flow cytometry analysis can be subjective. Since PMN-MDSC may not withstand freezing and thawing, analysis of this population may only be valid on freshly collected sampled. Therefore MDSC-based biomarker discovery efforts necessitate strict adherence to a clearly stated protocol that should be reproducible.
ROLE OF MDSC IN SOLID TUMORS
MDSC are pro-tumorigenic, and cancers appear to promote the differentiation of myeloid progenitors into MDSC. Both PMN-MDSC and M-MDSC, through the mechanisms detailed above, suppress anti-tumor immune activity. Specifically, MDSC inhibit cytotoxic T cells and natural killer cells and promote the expansion of regulatory T cells  Additionally, Ortiz et al. found that MDSC promote melanoma carcinogenesis in a murine carcinogen model via specific recruitment of IL-17 producing CD4+ T cells . In turn, the mechanisms by which MDSC are induced by cancers include tumor-derived growth factors (such as GM-CSF), tumor stroma-produced cytokines (such as IL-6) and hypoxia [9, 28].
As a quantitative biomarker, MDSC are an adverse prognostic factor in cancer patients. Markowitz et al. studying a cohort of patients with pancreatic adenocarcinoma, found that patients with progressive disease had higher levels of circulating CD33+HLA-DRneg MDSC . A 2016 meta-analysis performed by Zhang et al. combined 442 patients with different types of solid tumors (including hepatocellular carcinoma, melanoma and colorectal cancer) and evaluated the data regarding circulating MDSC levels and overall survival. They demonstrated that MDSC quantity is an adverse prognostic factor, as patients with elevated MDSC levels exhibited a significantly increased hazard of death from any cause . A report analyzing a large cohort of patients with breast cancer also associated higher circulating MDSC levels with worse overall survival . Li et al. studied a clinical cohort of ovarian cancer patients and reported that users of the anti-diabetic biguanide drug metformin had greater overall survival compared to non-users; performing in vitro studies of MDSC isolated from ovarian cancer patients, they demonstrated that metformin inhibited MDSC signaling via the AMKα/HIF1α pathway .
MDSC may also be predictive of response to therapy. Kitano et al. reported a novel method of quantifying MDSC via a computational algorithm that reproducibly classified CD11b+CD14+ MDSC as HLA-DRlow/neg, and found that low MDSC levels were associated with longer overall survival among a pooled clinical trial-based cohort of melanoma patients treated with the anti-CTLA-4 monoclonal antibody ipilimumab . Weber et al. found that high circulating MDSC levels (defined as >12.6% of CD14+CD11b+HLA-DRlow cells among viable peripheral blood mononuclear cells) was associated with substantially increased overall survival in ipilimumab-refractory melanoma patients treated with nivolumab .
Just as MDSC are related to prognosis among patients with many different tumor types, MDSC themselves may be modulated/inhibited by tumor-directed therapies. Elements that drive MDSC development include endoplasmic reticulum stress and the transcription factors STAT3, IRF8 and C/EBPβ [7, 8]. Cancer therapies that are thought to modulate MDSC include tyrosine kinase inhibitors (TKI) such as sunitinib [35–39] and sorafenib; [40–44] vascular endothelial growth factor (VEGF) inhibitors such as bevacizumab;  mammalian target of rapamycin (mTOR) inhibitors; [46–50] deacetylase (HDAC) inhibitors; [51, 52] fibroblast growth factor receptor (FGFR) inhibitors; [48, 53] chemotherapeutic agents such as gemcitabine,  5-fluorouracil (5-FU), [55–58] and cisplatin;  and radiation therapy [39, 60]. Clinical trials in bladder cancer that have investigated these agents are presented in Table S1.
EVIDENCE SUGGESTING TARGETING MDSC CAN ENHANCE CANCER IMMUNOTHERAPY
In addition to playing roles in carcinogenesis and conferring adverse oncologic outcomes, MDSC are also thought to underlie resistance to different types of cancer therapies. Several investigators have shown that the therapeutic efficacy of anti-PD-(L)1 or anti-CTLA-4 immune checkpoint blockade can be meaningfully increased in pre-clinical models that employ an MDSC-inhibiting strategy. MDSC targeting approaches in these studies have included histamine  TGFβ inhibition,  phenformin (an anti-diabetic biguanide)  CXCR2 inhibition,  sorafenib,  all-trans-retinoic-acid (ATRA),  ibrutinib (an inhibitor of the Bruton’s tyrosine kinase pathway in MDSC),  inhibition of CSF-1R,  PI3K inhibition, [68, 69] entinostat (a HDAC inhibitor),  bromodomain inhibition, [70, 71] CCRK inhibition,  and activation of Liver-X receptors (LXR) . These agents, along with the disease settings and/or models in which they were investigated, as well as applicable immunotherapies with which they were evaluated, are summarized in Table 1.
|Agent||Target/Mechanism||Setting||Evaluated in combination with|
|Histamine ||Myeloid cell NADPH oxidase (NOX2)||EL-4 (lymphoma), 4T1 (breast), MC38 (colon) [murine]||Anti-PD-1|
|TGF-βR Inhibitor ||TGF-β||EC109 esophageal squamous cell carcinoma [murine]||Anti-PD-1|
|Phenformin ||Biguanide (mitochondrial complex I)||BP01 melanoma [murine]||Anti-PD-1|
|Anti-CXCR2 mAb ||CXCR2||M3-9-M rhabdomyosarcoma [murine]||Anti-PD-1|
|Sorafenib ||Tyrosine kinase inhibitor (VEGFR, PDGFR, c-kit)||RENCA (renal cell carcinoma) [murine]||Anti-CTLA-4|
|All-trans-retinoic acid (ATRA) ||Decrease in circulating MDSC||Melanoma [human]||Anti-CTLA-4|
|Ibrutinib ||Bruton’s tyrosine kinase, IL-2-inducible T cell kinase||EMT6 (breast), 4T1 (breast) [murine]||Anti-PD-L1|
|Anti-B7-H3 mAb ||Decrease in circulating and intra-tumoral MDSC||Tgfbr1/Pten 2cKO Head and neck squamous cell carcinoma [murine]|
|IPI-145 ||PI3Kδ, PI3Kγ||MOC Head and neck squamous cell carcinoma [murine]||Anti-PD-L1|
|IPI-549 ||PI3Kγ (polarization of tumor associated myeloid cells from M2 to M1 phenotype)||4T1 (breast), B16 (melanoma), B16-GMCSF (melanoma) [murine]||Anti-PD-1 +/–Anti-CTLA-4|
|Eninostat ||Class I HDACs (inhibiting PMN-MDSC differentiation and function)||RENCA (renal cell carcinoma), LLC (lung carcinoma) [murine]||Anti-PD-1|
|JQ1 ||Bromodomain proteins (BRD2, BRD4, BRD9)||AB1 Malignant mesothelioma [murine]|
|PLX51107 ||Bromodomain proteins, Myc||EMT6 (breast) [murine]||Anti-CTLA-4|
|CCRK KO ||Inhibition of CCRK-mediated IL-6 (MDSC promoting cytokine)||Hepa1-6 (hepatocellular carcinoma) [murine]||Anti-PD-L1|
|RGX-104 ||Liver-X receptor (LXR)/ApoE agonist||Multiple tumor types [murine]||Anti-PD-1, Adoptive T cell transfer, Gvax|
CORRELATIVE AND FUNCTIONAL CHARACTERIZATION OF MDSC IN BLADDER CANCER
Early pre-clinical evidence implicating a role for MDSC in the progression of bladder cancer was demonstrated by Eruslanov et al. who showed the SW780 bladder cancer xenografts in nu/nu mice were infiltrated with CD11b+Ly6C+ MDSC . The authors also identified prostaglandin E2 (PGE2) produced from cancer cells as a factor that promoted the differentiation of myeloid progenitors to MDSC, which had been previously observed in a different (4T1) tumor model by Sinha et al. . Prima et al. further defined the role of PGE2 in bladder cancer-associated MDSC. Studying murine MBT2 bladder cancer cells co-cultured with bone marrow cells, the authors found that tumor cells induced PD-L1 expression specifically on MDSC and tumor-associated macrophages, and that this PD-L1 expression was dependent on COX2 and PGE2 signaling .
Additional clinical evidence demonstrating the presence of MDSC within bladder cancers was shown by Brandau et al. in 2011 . Among a cohort of patient with different tumor types, 16 patients with urothelial cancers were found to have elevated circulating quantities of CD33+HLD-DR- MDSC, which were found to also have the capacity to inhibit T cell proliferation and IFNγ production from patient-derived T cells . Adding insight into the suppressive mechanisms of MDSC in bladder cancer, Yuan et al. showed that the ability of bladder cancer patient-derived CD14+HLA-DR–/low MDSC to decrease peripheral blood mononuclear cell-mediated IFNγ production could be reversed by supplementation with L-arginine or anti-TGFβ. This finding demonstrated the potential importance of canonical MDSC mechanisms (arginase, TGF-β secretion) in bladder cancer .
Zamanian-Daryoush showed in an immune competent MB49 model of bladder cancer that subcutaneous allograft growth was significantly diminished in the setting of myeloid-specific conditional knockout of the ABCA1 cholesterol transporter,  suggesting lipoprotein metabolism as a determinant of MDSC tumor-promoting function. Zhang and Chin, studying a murine MB49 orthotopic model of bladder cancer, found that transgenic mice deficient for the kinase Rip2 had tumors that were much larger, highly infiltrated with MDSC and, compared with Rip2-competent subjects, had higher intratumoral levels of G-CSF. Thus Rip2 may be part of a signaling axis necessary for MDSC recruitment .
MDSC may also inhibit the adaptive arm of the tumor immune response in bladder cancer. Bennet et al. found in a 1978 report that bone-marrow-derived ‘natural suppressor cells’ from BCG-immunized mice could inhibit cell-mediated immunity against allogeneic tumor cells . Smith et al. studied a murine MB49 orthtopic model of bladder cancer and found that one of the correlates of successful treatment and tumor immunity induced by an IL-12 based intravesical treatment was decreased MDSC in the bladder .
MDSC AND BLADDER CANCER STAGE
Several studies indicate that MDSC quantities are directly associated with increasing stage in bladder cancer patients. Initially, Eruslanov et al. made the qualitative observation that MDSC, paradoxically, were more highly infiltrative into non-muscle invasive bladder cancers than invasive bladder cancers . However, the strength of these results was limited by small sample size. In a different study that analyzed 113 bladder cancer patients, Yang et al. found that CD11b+CD33lowHLA-DR- circulating MDSC quantities were higher in patients harboring high grade malignancies (p = 0.009) and in those with high stage disease (pT2-4, p < 0.0001) . Among a contemporary cohort of 36 patients with invasive localized bladder cancer undergoing neoadjuvant chemotherapy (predominantly cisplatin-based) followed by radical cystectomy, the quantity of circulating CD33+HLA-DR– MDSC was significantly lower among patients who were found to be complete responders to neoadjuvant therapy (defined as stage pT0N0 at radical cystectomy) .
MDSC AND BLADDER CANCER PROGNOSIS
MDSC are directly associated with adverse oncologic outcomes in clinical bladder cancer cohorts. Controlling for clinical and pathologic variables in a multivariable Cox proportional hazards analyses, multiple groups have found that a high quantity of MDSC (either circulating or infiltrating the tumor) is significantly associated with a higher hazard of death [84, 86]. The previously referenced study by Ornstein et al. while strictly describing an association of MDSC quantity with pathologic stage after neoadjuvant chemotherapy  nevertheless provides an additional indicator that MDSC may be prognostic due to the fact that response to neoadjuvant chemotherapy is a well-validated predictor of favorable survival after radical cystectomy . Recently, Tzeng et al. analyzed a cohort of 41 patients with metastatic urothelial carcinoma treated with systemic anti-PD-1 or anti-PD-L1 immune checkpoint blockade; their analysis did not show MDSC to be a prognostic biomarker. But these authors did find that patients undergoing anti-PD-1 treatment sustained a decrease in PD-1+ MDSC after therapy, and patients undergoing anti-PD-L1 treatment, similarly, sustained a decreased in PD-L1+ MDSC after therapy .
MDSC have even been found to be predictive of response among patients undergoing intravesical Bacille-Calmette Guerin (BCG) immunotherapy for high-risk non-muscle invasive bladder cancer. Chevalier et al. isolated CD33+CD11b+HLA-DRlow MDSC, among other immune cell populations, from the urine of patients before and after BCG therapy. The authors discovered that patients with urinary MDSC:T cell ratios >1 experienced substantially lower recurrence-free and progression-free survival; that pre-treatment and post-treatment MDSC:T cell ratios did not appreciably change after BCG therapy; and that resistance to BCG may be mediated by type 2 innate lymphoid cells (ILC2), which promote the recruitment and immune suppressive functions of MDSC via IL-13 .
IMPACT OF BLADDER CANCER TREATMENTS ON MDSC
Emerging evidence suggests that multiple types of bladder cancer directed therapies in clinical use can modulate MDSC, which may in part explain their effectiveness. For patients with high-risk non-muscle invasive bladder cancers (‘superficial’ high grade stage cTis, cTa and cT1 bladder cancers that are associated with high recurrence rates), the gold standard treatment is immunotherapy with Bacille-Calmette Guerin (BCG). BCG is a live attenuated bacterium, Mycobacterium bovis, that induces infiltration of activated CD4+ and CD8+ T cells into the bladder with repeated intravesical instillations 
Wang et al. studied the effect of intravesical BCG administered to Sprague-Dawley rats that had developed endogenous orthotopic bladder cancers after exposure to the carcinogen N-methyl-N-nitrosurea (MNU). They demonstrated that intravesical BCG and systemic anti-PD-L1 therapy independently and synergistically decreased the quantity of CD11b+Gr-1+ MDSC in tumor-bearing bladders . A decrease in intratumoral MDSC was also demonstrated with anti-PD-L1 therapy in the murine subcutaneous MB49 model by Shao et al. . Similarly, Huang et al. showed in C3H mice with orthotopically implanted MBT2 bladder cancers that the quantity of circulating CD11b+Gr-1+ MDSC was decreased in dose dependent fashion with intravesical BCG instillations . On balance, others have shown that BCG may induce bladder cancer cells to secrete MDSC-attracting chemokines. Muthuswamy et al. studied an in vitro model system consisting of TS4 bladder cancer cells, fibroblasts and CD14+ monocytes isolated from blood; in this model, BCG was associated with increased supernatant concentrations of CXCL8 and CCL22, which are MDSC chemoattractants . As discussed in the prior section, systemic BCG has been reported to promote ‘natural suppressor cells’ that inhibit cell-mediated immunity as well . Therefore there is conflicting data as to whether BCG promotes or antagonizes MDSC in the bladder cancer microenvironment.
Cisplatin is the foundation of frontline systemic chemotherapy regimens for patients with locally advanced or metastatic bladder cancers. Wu et al. studied the effect of in vitro cisplatin administration on peripheral blood mononuclear cells isolated from patients with bladder cancer and found a decrease in CD33+CD11b+CD14–CD15+ PMN-MDSC . In this study it was also observed that cisplatin-pretreated PMN-MDSC had a diminished ability to suppress CD8+ T cell proliferation,  suggesting that the therapeutic effect of cisplatin in bladder cancer may be due in part to its deleterious effects on PMN-MDSC number and function.
Gemcitabine chemotherapy is another fundamental component of cytotoxic chemotherapy regimens directed against bladder cancers (frequently in combination with cisplatin) in the neoadjuvant, adjuvant, and metastatic settings; and its use also extends to intravesical instillations in patients with localized, low-grade non-muscle invasive bladder cancers . Gemcitabine has also been shown to inhibit MDSC. Studying several cancer types in immunocompetent murine models, Suzuki et al. showed that splenic CD11b+/Gr-1+ MDSC were substantially decreased after gemcitabine treatment of tumor-bearing subjects and enhanced the therapeutic efficacy of intratumoral IFN-β . Gemcitabine may also decrease the prevalence of tumor-infiltrating CD11b+/Gr-1+ MDSC, as reported by Sawant et al. who were studying the combination of gemcitabine plus superoxide dismutase in the Lewis Lung murine lung carcinoma model . Finally, as discussed previously, gemcitabine has been shown to decrease CD11b+/CD14–/CD33+/HLA-DR– PMN-MDSC levels in the circulation of patients with pancreatic cancer .
5-fluorouracil (5-FU), when used with cisplatin or mitomycin, is a commonly used radio-sensitizing chemotherapy agent administered to patients with invasive bladder cancer who opt for a radiation therapy based bladder-sparing approach . Liljenfeldt et al. explored the effect of intratumoral MDSC when C57BL/6 mice with orthotopic MB49 bladder cancers were administered 5-FU +/–CD40L expressing adenovirus (CD40L is an activator of antigen presenting cells) . The authors noted that the combination treatment regimen (5-FU plus Ad-CD40L) led to a significant increase in the ratio of Gr-1high:Gr-1intermediate MDSC. Because it had been previously demonstrated that Gr-1int MDSC were more suppressive to T cell proliferation than Gr-1high MDSC,  Liljenfeldt et al. associated the efficacy of 5-FU plus Ad-CD40L with that particular regimen’s effect on suppressive MDSC. The ability of 5-FU to decrease MDSC number and function has also been observed in a murine colorectal carcinoma model .
Systemic treatments for patients with bladder cancer include monoclonal antibodies that target immune checkpoints such as PD-1, PD-L1, and CTLA-4. The PD-1 inhibitor nivolumab is an FDA-approved agent for patients with bladder cancer whose disease has progressed after treatment with cisplatin-based chemotherapy. Updated results of the Checkmate 275 trial (platinum-resistant urothelial carcinoma) reported by Sharma et al. suggest that high baseline MDSC levels are associated with lower survival after nivolumab treatment  While baseline MDSC levels may be predictive, they may not necessarily change after systemic therapy. Galsky et al. demonstrated in a phase 2 cohort of patients with urothelial carcinoma treated with two cycles of gemcitabine/cisplatin followed by four cycles of gemcitabine/cisplatin in combination with the anti-CTLA-4 monoclonal antibody ipilimumab found that neither circulating PMN-MDSC nor M-MDSC levels changed after chemotherapy or chemo-immunotherapy .
Nutritional interventional has been recently studied among patients with bladder cancer, along with effects on MDSC. Hamilton-Reeves et al. reported on a group of 29 men with bladder cancer undergoing radical cystectomy. Patients were randomized to peri-operative oral intake of a standard versus arginine-supplemented nutritional product. The arginine-supplemented product was found to be associated with a significantly lower quantity of circulating CD11b+CD33+LIN–CD14+CD15– M-MDSC two days after surgery and a slightly lower rate of post-operative infectious complications .
CLINICAL TRIALS INVESTIGATING AGENTS WITH POTENTIAL MDSC EFFECTS
MDSC signaling can be modulated by a wide range of pharmacologic agents, as reviewed by Wesolowski et al.  and as discussed in the preceding sections. Clinical trials investigating systemic therapies for bladder cancer in the metastatic and salvage settings (up to date as of December 2018), registered on ClinicalTrials.gov, that include agents known to modulate MDSC, are summarized in Table S1.
An example of a protocol that incorporates an MDSC-inhibiting chemotherapy (cisplatin) with a PD-1 inhibitor (pembrolizumab) is NCT02662062 – this phase 2 trial sponsored by Australian and New Zealand Urogenital and Prostate Trials Group also assesses radiation therapy as a bladder-sparing alternative to radical cystectomy. NCT02351739 is an example of a clinical trial that investigates the use of a tyrosine kinase inhibitor (acalabrutinib) that regulates Bruton’s Tyrosine Kinase signaling (which is a key functional pathway in MDSC ) in combination with pembrolizumab – this combination is being evaluated in patients with metastatic urothelial carcinoma whose tumors progressed after first line cisplatin-based chemotherapy regimens. These notable trials are listed among the comprehensive list in Table S1. Any preliminary or final results regarding response and survival rates posted on ClinicalTrials.gov or published as papers or abstracts are included in the table summary.
MDSC IN BLADDER CANCER: FUTURE RESEARCH PRIORITIES
Taken together, MDSC represent a second immune checkpoint that may form the basis of intrinsic therapeutic resistance of most bladder cancers to anti-PD-(L)1 immunotherapy, BCG intravesical immunotherapy and cisplatin-based chemotherapies. Therefore targeting MDSC may be relevant for multiple states of bladder cancer. A notable unmet clinical need is for patients with non-muscle invasive bladder cancers that are unresponsive to intravesical BCG [107, 108]. It has not yet been established that MDSC underlie BCG resistance for this particular disease state. As reviewed above, MDSC infiltration may predict response to BCG, but BCG may either promote or antagonize MDSC. Therefore a combination strategy where BCG is given in sequence after an MDSC-depleting therapy (such as gemcitabine, a well-established intravesical bladder-cancer treatment)  may be appropriate for future pre-clinical and clinical study.
For patients with localized muscle-invasive bladder cancers (cT2-4 N0), cisplatin is the mainstay of combination chemotherapy regimens in the neoadjuvant setting. Cisplatin-based chemotherapy regimens are also the frontline treatments administered to patients with metastatic bladder cancer. Because cisplatin has been suggested to deplete circulating MDSC, current combination chemo-immunotherapy trials (cisplatin plus anti-PD-(L)1 therapy) (listed in Table 1) may offer promising response rates; non-responders in these clinical trials may reveal redundant MDSC signaling pathways that persist despite cisplatin.
Beyond general strategies to inhibit MDSC in the setting of bladder cancer, it is important to recognize that the subtypes of MDSC that promote bladder carcinogenesis, progression and therapeutic resistance may be uniquely driven by bladder cancer-specific signaling derived from epithelial and stromal compartments of the tumor. For this reason, basic science efforts to delineate dominant signaling pathways in bladder cancer derived MDSC may generate unique insights to enhance systemic therapy for this disease.
The authors report no funding.
CONFLICT OF INTEREST
The authors have no conflict of interest to report.
The authors have no acknowledgments.
Galsky MD , Hahn NM , Rosenberg J , et al. Treatment of patients with metastatic urothelial cancer “Unfit” for cisplatin-based chemotherapy. J Clin Oncol. 2017;29(17):2432–8. doi: 10.1200/JCO.2011.34.8433
Balar AV , York N . Immune checkpoint blockade in metastatic urothelial cancer. J Clin Oncol. 2017;35(19):2109–12.
Bellmunt J , de Wit R , Vaughn DJ , et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26. doi: 10.1056/NEJMoa1613683
Kamat AM , Bellmunt J , Galsky MD , et al. Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma. J Immunother Cancer. 2017:1–16. doi: 10.1186/s40425-017-0271-0
Gabrilovich DI . Myeloid-derived suppressor cells. Cancer Immunol Res. 2017;5(1):3–9. doi: 10.1158/2326-6066.CIR-16-0297
Talmadge JE , Gabrilovich DI . History of myeloid-derived suppressor cells. Nat Rev Cancer. 2013;13:739–52. doi: 10.1038/nrc3581
Tcyganov E , Mastio J , Chen E , Gabrilovich DI . Plasticity of myeloid-derived suppressor cells in cancer. Curr Opin Immunol. 2018;51:76–82.
Mony S , Alicea-torres K , Tcyganov E , et al. Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci Immunol. 2017;1(2):1–32. doi: 10.1126/sciimmunol.aaf8943.Lectin-type
Kumar V , Cheng P , Condamine T , et al. CD45 phosphatase inhibits STAT3 transcription factor activity in myeloid cells and promotes tumor- associated macrophage differentiation article CD45 phosphatase inhibits STAT3 transcription factor activity in myeloid cells and promotes tumor-associated M. Immunity. 2016;44:303–15. doi: 10.1016/j.immuni.2016.01.014
Cassetta L , Baekkevold ES , Brandau S , Bujko A , Cassatella MA , Dorhoi A . Deciphering myeloid-derived suppressor cells: Isolation and markers in humans, mice and non-human primates. Cancer Immunol Immunother. 2019: In press. doi: 10.1007/s00262-019-02302-2
Dorhoi A , Du Plessis N . Monocytic myeloid-derived suppressor cells in chronic infections. Front Immunol. 2018;8:1–15. doi: 10.3389/fimmu.2017.01895
Veglia F , Perego M , Gabrilovich D . Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018;19:108–19. doi: 10.1038/s41590-017-0022-x
Mundy-Bosse BL , Lesinski GB , Jaime-ramirez AC , et al. Myeloid-derived suppressor cell inhibition of the IFN response in tumor-bearing mice. Cancer Res. 2011;71(15):5101–10. doi: 10.1158/0008-5472.CAN-10-2670
Kostlin N , Kugel H , Spring B , et al. Granulocytic myeloid derived suppressor cells expand in human pregnancy and modulate T-cell responses. Eur J Immunol. 2014;44:2582–91. doi: 10.1002/eji.201344200
Köstlin N , Hofstädter K , Ostermeir A , et al. Granulocytic myeloid-derived suppressor cells accumulate in human placenta and polarize toward a Th2 phenotype. J Immunol. 2016;196:1132–45. doi: 10.4049/jimmunol.1500340
Hurez V , Padrón Á , Svatek RS , Curiel TJ . Considerations for successful cancer immunotherapy in aged hosts. Exp Gerontol. 2018;107(September 2017):27–36. doi: 10.1016/j.exger.2017.10.002
Verschoor CP , Johnstone J , Millar J , et al. Blood CD33(+)HLA-DR(-) myeloid-derived suppressor cells are increased with age and a history of cancer. J Leukoc Biol. 2013;93(April):633–7. doi: 10.1189/jlb.0912461
Ostrand-Rosenberg S . Myeloid derived-suppressor cells: Their role in cancer and obesity. Curr Opin Immunol. 2018;51:68–75. doi: 10.1016/j.coi.2018.03.007
Clements VK , Figley C , Smith DMC , Ostrand-rosenberg S . High fat diet and leptin promote tumor progression by inducing myeloid-derived suppressor cells. J Leukoc Biol. 2018395–407. doi: 10.1002/JLB.4HI0517-210R
Crook KR , Jin M , Weeks MF , et al. Myeloid-derived suppressor cells regulate T cell and B cell responses during autoimmune disease. J Leukoc Biol. 2015;97:573–82. doi: 10.1189/jlb.4A0314-139R
Meng F , Chen S , Guo X , et al. Clinical significance of myeloid-derived suppressor cells in human renal transplantation with acute T cell-mediated rejection. Inflammation. 2014;37(5):1799–805. doi: 10.1007/s10753-014-9910-5
Wu T , Sun C , Chen Z , et al. Smad3-deficient CD11b+Gr1+myeloid-derived suppressor cells prevent allograft rejection via the nitric oxide pathway. J Immunol. 2012;189(10):4989–5000. doi: 10.4049/jimmunol.1200068
Vlkova M , Chovancova Z , Nechvatalova J , et al. Neutrophil and granuloytic myeloid-derived suppressor cell-mediated T cell suppression significantly contributes to immune dysregulation in common variable immunodeficiency disorders. J Immunol. 2018:In press. doi: 10.4049/jimmunol.1800102
Salminen A , Kaarniranta K , Kauppinen A . The potential importance of myeloid-derived suppressor cells (MDSCs) in the pathogenesis of Alzheimer’s disease. Cell Mol Life Sci. 2018;75:3099–120.
Bronte V , Brandau S , Chen S , et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7(12150):1–10. doi: 10.1038/ncomms12150
Wesolowski R , Markowitz J , Iii WEC . Myeloid derived suppressor cells – a new therapeutic target in the treatment of cancer. J Immunother Cancer. 2013;1(10):1–11.
Ortiz ML , Kumar V , Martner A , et al. Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17–producing CD4 + T cells. J Exp Med. 2015;212(3):351–67. doi: 10.1084/jem.20140835
Condamine T , Mastio J , Gabrilovich DI . Transcriptional regulation of myeloid-derived suppressor cells. J Leukoc Biol. 2015;98(6):913–22. doi: 10.1189/jlb.4RI0515-204R
Markowitz J , Brooks TR , Duggan MC , et al. Patients with pancreatic adenocarcinoma exhibit elevated levels of myeloid-derived suppressor cells upon progression of disease. Cancer Immunol Immunother. 2014;64(2):149–59. doi: 10.1007/s00262-014-1618-8
Zhang S , Ma X , Zhu C , Liu L , Wang G , Yuan X . The role of myeloid-derived suppressor cells in patients with solid tumors: A meta-analysis. PLoS One. 2016;11(10):1–11. doi: 10.1371/journal.pone.0164514
Gonda K , Shibata M , Ohtake T , et al. Myeloid-derived suppressor cells are increased and correlated with type 2 immune responses, malnutrition, inflammation, and poor prognosis in patients with breast cancer. Oncol Lett. 2017;14:1766–74.
Li L , Wang L , Li J , et al. Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer. Cancer Res. 2018;78(7):1779–91. doi: 10.1158/0008-5472.CAN-17-2460
Kitano S , Postow MA , Ziegler CGK , et al. Computational algorithm-driven evaluation of monocytic myeloid-derived suppressor cell frequency for prediction of clinical outcomes. Cancer Immunol Res. 2014;4(August):812–22. doi: 10.1158/2326-6066.CIR-14-0013
Weber J , Gibney G , Kudchadkar R , et al. Phase I / II study of metastatic melanoma patients treated with nivolumab who had progressed after ipilimumab. Cancer Immunol Res. 2016;1:345–54. doi: 10.1158/2326-6066.CIR-15-0193
Ko JS , Rayman P , Ireland J , et al. Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Res. 2010;70(9):3526–36. doi: 10.1158/0008-5472.CAN-09-3278
Guislain A , Gadiot J , Kaiser A , et al. Sunitinib pretreatment improves tumor-infiltrating lymphocyte expansion by reduction in intratumoral content of myeloid-derived suppressor cells in human renal cell carcinoma. Cancer Immunol Immunother. 2015;64(10):1241–50. doi: 10.1007/s00262-015-1735-z
Draghiciu O , Nijman HW , Hoogeboom BN , Meijerhof T , Daemen T . Sunitinib depletes myeloid-derived suppressor cells and synergizes with a cancer vaccine to enhance antigen-specific immune responses and tumor eradication. Oncoimmunology. 2015;4(3):1–11. doi: 10.4161/2162402X.2014.989764
van Hooren L , Georganaki M , Huang H , Mangsbo SM , Dimberg A . Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment. Oncotarget. 2016;7(31). doi: 10.18632/oncotarget.10364
Chen H , Ma G , Gildener-leapman N , et al. Myeloid-derived suppressor cells as an immune parameter in patients with concurrent sunitinib and stereotactic body radiotherapy. Clin Cancer Res. 2015;21(18):4073–86. doi: 10.1158/1078-0432.CCR-14-2742
Kapanadze T , Gamrekelashvili J , Ma C , et al. Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma. J Hepatol. 2013;59(5):1007–13. doi: 10.1016/j.jhe2013.06.010
Motoshima T , Komohara Y , Horlad H , et al. Sorafenib enhances the antitumor effects of anti-CTLA-4 antibody in a murine cancer model by inhibiting myeloid-derived suppressor cells. Oncol Rep. 2015;33(6):2947–53. doi: 10.3892/or.2015.3893
Ho V , Lim TS , Lee J , et al. TLR3 agonist and Sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression. Oncotarget. 2015;6(29). doi: 10.18632/oncotarget.4583
Martin del Campo SE , Levine KM , Mundy-Bosse BL , et al. The raf kinase inhibitor sorafenib inhibits JAK–STAT signal transduction in human immune cells. J Immunol. 2015;195(5):1995–2005. doi: 10.4049/jimmunol.1400084
Heine A , Schilling J , Grünwald B , et al. The induction of human myeloid derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib. Cancer Immunol Immunother. 2016;65(3):273–82. doi: 10.1007/s00262-015-1790-5
Feng PH , Chen KY , Huang YC , et al. Bevacizumab reduces S100A9-positive MDSCs linked to intracranial control in patients with EGFR-mutant lung adenocarcinoma. J Thorac Oncol. 2018;13(7):958–67. doi: 10.1016/j.jtho.2018.03.032
Wu T , Zhao Y , Wang H , et al. MTOR masters monocytic myeloid-derived suppressor cells in mice with allografts or tumors. Sci Rep. 2016;6(February):1–15. doi: 10.1038/srep20250
Huijts CM , Santegoets SJ , de Jong TD , Verheul HM , de Gruijl TD , van der Vliet HJ . Immunological effects of everolimus in patients with metastatic renal cell cancer. Int J Immunopathol Pharmacol. 2017;30(4):341–52. doi: 10.1177/0394632017734459
Welte T , Kim IS , Tian L , et al. Oncogenic mTOR signalling recruits myeloid-derived suppressor cells to promote tumour initiation. Nat Cell Biol. 2016;18(6):632–44. doi: 10.1038/ncb3355
Deng Y , Yang J , Luo F , et al. mTOR-mediated glycolysis contributes to the enhanced suppressive function of murine tumor-infiltrating monocytic myeloid-derived suppressor cells. Cancer Immunol Immunother. 2018;67(9):1355–64. doi: 10.1007/s00262-018-2177-1
Lin Y , Wang B , Shan W , et al. mTOR inhibitor rapamycin induce polymorphonuclear myeloid-derived suppressor cells mobilization and function in protecting against acute graft-versus-host disease after bone marrow transplantation. Clin Immunol. 2018;187:122–31. doi: 10.1016/j.clim.2017.11.005
Wang HF , Ning F , Liu ZC , et al. Histone deacetylase inhibitors deplete myeloid-derived suppressor cells induced by 4T1 mammary tumors in vivo and in vitro. Cancer Immunol Immunother. 2017;66(3):355–66. doi: 10.1007/s00262-016-1935-1
Orillion A , Hashimoto A , Damayanti N , et al. Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. Clin Cancer Res. 2017;23(17):5187–201. doi: 10.1158/1078-0432.CCR-17-0741
Ye T , Wei X , Yin T , et al. Inhibition of FGFR signaling by PD173074 improves antitumor immunity and impairs breast cancer metastasis. Breast Cancer Res Treat. 2014;143(3):435–46. doi: 10.1007/s10549-013-2829-y
Eriksson E , Wenthe J , Irenaeus S , Loskog A , Ullenhag G . Gemcitabine reduces MDSCs, tregs and TGFβ-1 while restoring the teff/treg ratio in patients with pancreatic cancer. J Transl Med. 2016;14(1):282. doi: 10.1186/s12967-016-1037-z
Liljenfeldt L , Gkirtzimanaki K , Vyrla D , Svensson E , Si A , Eliopoulos AG . Enhanced therapeutic anti – tumor immunity induced by co – administration of 5 – fluorouracil and adenovirus expressing CD40 ligand. Cancer Immunol Immunother. 2014;63:273–82. doi: 10.1007/s00262-013-1507-6
Namdar A , ez Mirzaei HR , Jadidi-Niaragh F , et al. Multiple low doses of 5-fluorouracil diminishes immunosuppression by myeloid derived suppressor cells in murine melanoma model. Iran J Immunol. 2015;12(3):176–87. doi: IJIv12i3A3
Abedi-Valugerdi M , Wolfsberger J , Pillai PR , et al. Suppressive effects of low-dose 5-fluorouracil, busulfan or treosulfan on the expansion of circulatory neutrophils and myeloid derived immunosuppressor cells in tumor-bearing mice. Int Immunopharmacol. 2016;40:41–9. doi: 10.1016/j.intim2016.08.023
Abedi-Valugerdi M , Zheng W , Benkessou F , Zhao Y , Hassan M . Differential effects of low-dose fludarabine or 5-fluorouracil on the tumor growth and myeloid derived immunosuppression status of tumor-bearing mice. Int Immunopharmacol. 2017;47(March):173–81. doi: 10.1016/j.intim2017.04.006
Wu K , Tan MY , Jiang JT , et al. Cisplatin inhibits the progression of bladder cancer by selectively depleting G-MDSCs: A novel chemoimmunomodulating strategy. Clin Immunol. 2018;193:60–9. doi: 10.1016/j.clim.2018.01.012
Finkelstein SE , Iclozan C , Bui M , et al. Combination of external beam radiotherapy (EBRT) with intratumoral injection of dendritic cells as neo-adjuvant treatment of high-risk soft tissue sarcoma patients. Int J Radiat Oncol Biol Phys. 2012;82(2):924–32. doi: 10.1016/j.ijrob2010.12.068
Grauers Wiktorin H , Nilsson MS , Kiffin R , et al. Histamine targets myeloid-derived suppressor cells and improves the anti-tumor efficacy of PD-1/PD-L1 checkpoint blockade. Cancer Immunol Immunother. 2018;(0123456789). doi: 10.1007/s00262-018-2253-6
Chen X , Wang L , Li P , et al. Dual TGF-β and PD-1 blockade synergistically enhances MAGE-A3-specific CD8+T cell response in esophageal squamous cell carcinoma. Int J Cancer. 2018;143(10):2561–74. doi: 10.1002/ijc.31730
Kim SH , Li M , Trousil S , et al. Phenformin inhibits myeloid-derived suppressor cells and enhances the anti-tumor activity of PD-1 blockade in melanoma. J Invest Dermatol. 2017;137(8):1740–8. doi: 10.1016/j.jid.2017.03.033
Highfill SL , Cui Y , Giles AJ , et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med. 2014;6(237):1–13.
Tobin RP , Jordan KR , Robinson WA , et al. Targeting myeloid-derived suppressor cells using all-trans retinoic acid in melanoma patients treated with Ipilimumab. Int Immunopharmacol. 2018;63(July):282–91. doi: 10.1016/j.intim2018.08.007
Stiff A , Trikha P , Wesolowski R , et al. Myeloid-derived suppressor cells express bruton’s tyrosine kinase and can be depleted in tumor-bearing hosts by ibrutinib treatment. Cancer Res. 2016;76(8):2125–37. doi: 10.1158/0008-5472.CAN-15-1490
Mao Y , Eissler N , Le Blanc K , Johnsen JI , Kogner P , Kiessling R . Targeting suppressive myeloid cells potentiates checkpoint inhibitors to control spontaneous neuroblastoma. Clin Cancer Res. 2016;22(15):3849–59. doi: 10.1158/1078-0432.CCR-15-1912
Davis RJ , Moore EC , Clavijo PE , et al. Anti-PD-L1 efficacy can be enhanced by inhibition of myeloid-derived suppressor cells with a selective inhibitor of PI3Kd/g. Cancer Res. 2017;77(10):2607–19. doi: 10.1158/0008-5472.CAN-16-2534
De Henau O , Rausch M , Winkler D , et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature. 2016;539(7629):443–7. doi: 10.1038/nature20554
Riganti C , Lingua M , Salaroglio I , et al. Bromodomain inhibition exerts its therapeutic potential in malignant pleural mesothelioma by promoting immunogenic cell death and changing the tumor. Oncoimmunology. 2018;7(3):1–13. doi: 10.1080/2162402X.2017.1398874
Lai X , Stiff A , Duggan M , Wesolowski R , Carson WE , Friedman A . Modeling combination therapy for breast cancer with BET and immune checkpoint inhibitors. Proc Natl Acad Sci. 2018;115(21):5534–9. doi: 10.1073/pnas.1721559115
Zhou J , Liu M , Sun H , et al. Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy. Gut. 2018;67(5):931–44. doi: 10.1136/gutjnl-2017-314032
Tavazoie MF , Pollack I , Tanqueco R , et al. Article LXR / ApoE activation restricts innate immune suppression in cancer article LXR / ApoE activation restricts innate immune suppression in cancer. Cell. 2018:825–40. doi: 10.1016/j.cell.2017.12.026
Eruslanov E , Daurkin I , Vieweg J , Daaka Y , Kusmartsev S . Aberrant PGE 2 metabolism in bladder tumor microenvironment promotes immunosuppressive phenotype of tumor-infiltrating myeloid cells. Int Immunopharmacol. 2011;11(7):845–52. doi: 10.1016/j.intim2011.01.033
Cells MS , Sinha P , Clements VK , Fulton AM , Ostrand-rosenberg S . Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. 2007(9):4507–14. doi: 10.1158/0008-5472.CAN-06-4174
Prima V , Kaliberova LN , Kaliberov S , Curiel DT , Kusmartsev S . COX2/mPGES1/PGE 2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proc Natl Acad Sci. 2017;114(5):1117–22. doi: 10.1073/pnas.1612920114
Brandau S , Trellakis S , Bruderek K , et al. Myeloid-derived suppressor cells in the peripheral blood of cancer patients contain a subset of immature neutrophils with impaired migratory properties. J Leukoc Biol. 2011;89(2):311–7. doi: 10.1189/jlb.0310162
Yuan X-K , Zhao X-K , Xia Y-C , Zhu X , Xiao P . Increased circulating immunosuppressive CD14 + HLA-DR –/Low cells correlate with clinical cancer stage and pathological grade in patients with bladder carcinoma. J Int Med Res. 2011;39(4):1381–91. doi: 10.1177/147323001103900424
Zamanian-Daryoush M , Lindner DJ , DiDonato JA , et al. Myeloid-specific genetic ablation of ATP-binding cassette transporter ABCA1 is protective against cancer. Oncotarget. 2017;8(42):71965–80. doi: 10.18632/oncotarget.18666
Zhang H , Chin AI . Role of Rip2 in development of tumor-infiltrating MDSCs and bladder cancer metastasis. PLoS One. 2014;9(4). doi: 10.1371/journal.pone.0094793
Bennett JA , Rao VS , Mitchell MS . Systemic bacillus Calmette-Guerin (BCG) activates natural suppressor cells. Proc Natl Acad Sci. 1978;75(10):5142–4.
Smith SG , Baltz JL , Koppolu BP , et al. Immunological mechanisms of intravesical chitosan/interleukin-12 immunotherapy against murine bladder cancer. Oncoimmunology. 2017;6(1):e1259050. doi: 10.1080/2162402X.2016.1259050
Eruslanov E , Neuberger M , Daurkin I , et al. Circulating and tumor-infiltrating myeloid cell subsets in patients with bladder cancer. Int J Cancer. 2012;130(5):1109–19. doi: 10.1002/ijc.26123
Yang G , Shen W , zhang Y , et al. Accumulation of myeloid-derived suppressor cells (MDSCs) induced by low levels of IL-6 correlates with poor prognosis in bladder cancer. Oncotarget. 2017;8(24):38378–88. doi: 10.18632/oncotarget.16386
Ornstein MC , A M , Diaz-montero CM , et al. Myeloid-derived suppressors cells (MDSC) correlate with clinicopathologic factors and pathologic complete response (pCR) in patients with urothelial carcinoma (UC) undergoing cystectomy. Urol Oncol Semin Orig Investig. 2018;36(9):405–12. doi: 10.1016/j.urolonc.2018.02.018
Zhang H , Ye YL , Li MX , et al. CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer. Oncogene. 2017;36(15):2095–104. doi: 10.1038/onc.2016.367
Lavery HJ , Stensland KD , Niegisch G , Albers P , Droller MJ . Pathological T0 following radical cystectomy with or without neoadjuvant chemotherapy: A useful surrogate. J Urol. 2014;191(April):898–906. doi: 10.1016/j.juro.2013.10.142
Tzeng A , Diaz-montero CM , Rayman PA , et al. Immunological correlates of response to immune checkpoint inhibitors in metastatic urothelial carcinoma. Target Oncol. 2018;13:599–609.
Chevalier MF , Trabanelli S , Racle J , et al. ILC2-modulated T cell-to-MDSC balance is associated with bladder cancer recurrence. J Clin Invest. 2017;127(8):2916–29. doi: 10.1172/JCI89717
Biot C , Rentsch CA , Gsponer JR , et al. Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. Sci Transl Med. 2012;4(137):1–10.
Wang Y , Liu J , Yang X , et al. Bacillus Calmette–Guérin and anti-PD-L1 combination therapy boosts immune response against bladder cancer. Onco Targets Ther. 2018;11:2891–900.
Shao Y , Zhu W , Da J , et al. Bisdemethoxycurcumin in combination with α-PD-L1 antibody boosts immune response against bladder cancer. Onco Targets Ther. 2017;10:2675–83. doi: 10.2147/OTT.S130653
Huang P , Ma C , Xu P , Guo K , Xu A , Liu C . Efficacy of intravesical bacillus calmette-guérin therapy against tumor immune escape in an orthotopic model of bladder cancer. Exp Ther Med. 2015;9(1):162–6. doi: 10.3892/etm.2014.2060
Muthuswamy R , Wang L , Pitteroff J , Gingrich JR , Kalinski P . Combination of IFNα and poly-I: C reprograms bladder cancer microenvironment for enhanced CTL attraction. J Immunother Cancer. 2015;3(1):1–10. doi: 10.1186/s40425-015-0050-8
Wu K , Tan M , Jiang J , et al. Cisplatin inhibits the progression of bladder cancer by selectively depleting G-MDSCs: A novel chemoimmunomodulating strategy. Clin Immunol. 2018;In press.: 1–10. doi: 10.1016/j.clim.2018.01.012
Messing EM , Tangen CM , Lerner SP , et al. Effect of intravesical instillation of gemcitabine vs saline immediately following resection of suspected low-grade non-muscle-invasive bladder cancer on tumor recurrence SWOG S0337 randomized clinical trial. JAMA – J Am Med Assoc. 2018;319(18):1880–8. doi: 10.1001/jama.2018.4657
Suzuki E , Kapoor V , Jassar AS , Kaiser LR , Albelda SM . Gemcitabine selectively eliminates splenic Gr-1+/CD11b+myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res. 2005;11(18):6713–22. doi: 10.1158/1078-0432.CCR-05-0883
Sawant A , Schafer CC , Jin TH , et al. Enhancement of antitumor immunity in lung cancer by targeting myeloid-derived suppressor cell pathways. Cancer Res. 2013;73(22):6609–21. doi: 10.1158/0008-5472.CAN-13-0987
NCCN.org. National Comprehensive Cancer Network Clinical Practice Guidelines: Bladder Cancer. 2018. doi: 10.1038/551S33a
Dolcetti L , Peranzoni E , Ugel S , et al. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol. 2010;40(1):22–35. doi: 10.1002/eji.200939903
Kanterman J , Sade-feldman M , Biton M , et al. Adverse immunoregulatory effects of 5FU and CPT11 chemotherapy on myeloid-derived suppressor cells and colorectal cancer outcomes. Cancer Res. 2014;74(15):6022–36. doi: 10.1158/0008-5472.CAN-14-0657
Sharma P , Baron A , Necchi A , et al. Abstract CT Nivolumab monotherapy in patients with advanced platinum-resistant urothelial carcinoma: Efficacy and safety update and association between biomarkers and overall survival in CheckMate 275. Cancer Res. 2018;78(13 Supplement):CT178 LP-CT178. doi: 10.1158/1538-7445.AM2018-CT178
Galsky MD , Wang H , Hahn NM , et al. Urothelial cancer phase 2 trial of gemcitabine, cisplatin, plus ipilimumab in patients with metastatic urothelial cancer and impact of DNA damage response gene mutations on outcomes. Eur Urol. 2017;3:760–2.
Hamilton-Reeves JM , Bechtel MD , Hand LK , et al. Effects of immunonutrition for cystectomy on immune response and infection rates: A pilot randomized controlled clinical trial. Eur Urol. 2016;69(3):389–92. doi: 10.1016/j.eururo.2015.11.019
Wesolowski R , Markowitz J , Carson III WE . Myeloid derived suppressor cells – a new therapeutic target in the treatment of cancer. J Immunother Cancer. 2013;1:1–11.
Stiff A , Trikha P , Wesolowski R , et al. Myeloid-derived suppressor cells express Bruton’s tyrosine kinase and can be depleted in tumor-bearing hosts by ibrutinib treatment. Cancer Res. 2016;76(8):2125–36. doi: 10.1158/0008-5472.CAN-15-1490
Kamat AM , Sylvester RJ , Andreas B , et al. Definitions, end points, and clinical trial designs for non–muscle-invasive bladder cancer: Recommendations from the international bladder cancer group. J Clin Oncol. 2016;34(16):1935–44. doi: 10.1200/JCO.2015.64.4070
Kamat AM , Colombel M , Sundi D , et al. BCG-unresponsive non-muscle-invasive bladder cancer: Recommendations from the IBCG. Nat Rev Urol. 2017;14(4):244–55. doi: 10.1038/nrurol.2017.16
Dreicer R , Manola J , Schneider DJ , et al. Phase II trial of gemcitabine and docetaxel in patients with advanced carcinoma of the urothelium: A trial of the Eastern Cooperative Oncology Group. Cancer. 2003;97(11):2743–7. doi: 10.1002/cncr.11413
De Santis M , Wiechno PJ , Bellmunt J , et al. Vinflunine-gemcitabine versus vinflunine-carboplatin as first-line chemotherapy in cisplatin-unfit patients with advanced urothelial carcinoma: Results of an international randomized phase II trial (JASINT1). Ann Oncol. 2016;27(3):449–54. doi: 10.1093/annonc/mdv609
Agarwal N , Apolo AB , Tsao C-K , et al. Phase Ib/II trial of gemcitabine, cisplatin, and lenalidomide as first-line therapy in patients with metastatic urothelial carcinoma. Oncologist. 2014;19(9):915–6. doi: 10.1634/theoncologist.2014-0153
Choi YJ , Lee SH , Lee JL , et al. Phase II study of pemetrexed in combination with cisplatin in patients with advanced urothelial cancer: The PECULIAR study (KCSG 10-17). Br J Cancer. 2015;112(2):260–5. doi: 10.1038/bjc.2014.591
Highley MS , Griffiths GO , Uscinska BM , et al. A phase II trial of continuous 5-fluorouracil in recurrent or metastatic transitional cell carcinoma of the urinary tract. Clin Oncol. 2009;21(5):394–400. doi: 10.1016/j.clon.2009.01.011
Balar AV , Galsky MD , Rosenberg JE , et al. Atezolizumab as first-line therapy in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: A single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67–76. doi: 10.1016/S0140-6736(16)32455-2.Atezolizumab
Powles T , Durán I , van der Heijden MS , et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): A multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391;(10122):748–57. doi: 10.1016/S0140-6736(17)33297-X
Oudard S , Culine S , Vano Y , et al. Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2. Eur J Cancer. 2015;51(1):45–54. doi: 10.1016/j.ejca.2014.10.009
Hussain M , Daignault S , Agarwal N , et al. A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma. Cancer. 2014;120(17):2684–93. doi: 10.1002/cncr.28767
Choueiri TK , Ross RW , Jacobus S , et al. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012;30(5):507–12. doi: 10.1200/JCO.2011.37.7002
Hahn NM , Stadler WM , Zon RT , et al. Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier oncology group GU 04-75. J Clin Oncol. 2011;29(12):1525–30. doi: 10.1200/JCO.2010.31.6067
Geldart T , Chester J , Casbard A , et al. SUCCINCT: An open-label, single-arm, non-randomised, phase 2 trial of gemcitabine and cisplatin chemotherapy in combination with sunitinib as first-line treatment for patients with advanced urothelial carcinoma. Eur Urol. 2015;67:599–602. doi: https://doi.org/10.1016/j.eururo.2014.11.003
Philips GK , Halabi S , Sanford BL , Bajorin D , Small EJ . A phase II trial of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial tract carcinoma: Results of Cancer and Leukemia Group B (CALGB) 90102. Ann Oncol. 2009;20(January):1074–9.10.1093/annonc/mdn749
Gomez-Abuin G , Winquist E , Stadler WM , et al. A phase II study of PS-341 (Bortezomib) in advanced or metastatic urothelial cancer. A trial of the Princess Margaret Hospital and University of Chicago phase II consortia. Invest New Drugs. 2007;25(2):181–5.10.1007/s10637-006-9009-4
Necchi A , Giannatempo P , Mariani L , et al. PF-03446962, a fully-human monoclonal antibody against transforming growth-factor β (TGFβ) receptor ALK1, in pre-treated patients with urothelial cancer: An open label, single-group, phase 2 trial. Invest New Drugs. 2014;32(3):555–60. doi: 10.1007/s10637-014-0074-9
Porena M , Del Zingaro M , Lazzeri M , et al. Bacillus calmette-guérin versus gemcitabine for intravesical therapy in high-risk superficial bladder cancer: A randomised prospective study. Urol Int. 2010;84(1):23–7. doi: 10.1159/000273461