title: MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy.
abstract: Sunitinib is a receptor tyrosine kinase inhibitor (TKI) that is front-line therapy for metastatic renal cell carcinoma (mRCC). Its antitumor activity is related to its ability to block tumor cell and tumor vasculature cell signaling via several TKI receptors (i.e. vascular endothelial growth factor receptors VEGFRs, platelet-derived growth factors (PDGFs), and stem cell factors). Sunitinib also targets myeloid derived suppressor cells (MDSCs) significantly reducing their accumulation in the peripheral blood and reversing T cell (IFNγ) suppression in both mRCC patients and in murine tumor models. This reduction in immune suppression provides a rationale for combining sunitinib with immunotherapy for the treatment of certain tumor types. Despite these encouraging findings, however, we have observed that sunitinib has variable impact at reducing MDSCs and restoring T cell function within the tumor microenvironment. Given the immunosuppressive and proangiogenic activities of MDSC, it seems plausible that their persistence may contribute to the resistance that develops in sunitinib-treated patients. While sunitinib reduced tumor infiltrating MDSCs in Renca and CT26-bearing mice, coinciding with strong to modest decreases in tumor size respectively, it was ineffective at reducing MDSCs (<35% reduction in Gr1+CD11b+) or tumor burden in 4T1-bearing mice. Persistence of intratumor MDSCs was paralleled by depressed intratumor T cell IFNγ response and increased GM-CSF expression. Additionally, in vitro and in vivo experiments showed that GM-CSF prolongs survival of MDSCs, thus protecting them from the effects of sunitinib via a pSTAT5-dependent pathway. Although preliminary, there is evidence of intratumor MDSC resistance in some mRCC patients following sunitinib treatment. Intratumor MDSC persistence and T cell IFNγ response post nephrectomy in patients receiving sunitinib in a neoadjuvant setting are being compared to RCC patients undergoing nephrectomy without prior sunitinib treatment. Tumors from untreated patients showed suppressed T cell IFNγ response along with substantial expression of MDSCs (5% of total digested cells). Thus far, tumors from 5/8 neoadjuvant patients showed persistence of intratumor MDSCs and low T cell IFNγ production post sunitinib treatment, findings that parallel results from untreated tumors. In the remaining 3 neoadjuvant patients, intratumor MDSCs were detected at low levels which coincided with a T cell IFNγ response similar to that observed with normal donor peripheral T cells. GM-CSF's role in promoting MDSC survival in patient tumors is supported by the observation that GM-CSF is produced in short-term RCC cultures at levels capable of protecting MDSCs from sunitinib-induced cell death. Additionally, persistence of MDSC also may be associated with increased expression of proangiogenic proteins, such as MMP9, MMP8, and IL-8 produced by tumor stromal cells or infiltrating MDSCs. Indeed our findings suggest that the most dominate MDSC subset in RCC patients is the neutrophilic population that produces proangiogenic proteins. We propose that the development of sunitinib resistance is partly mediated by the survival of MDSCs intratumorally, thereby providing sustained immune suppression and angiogenesis.
authors.affiliation: Department Immunology, NE40, Cleveland Clinic College of Medicine of CWRU, Cleveland Clinic, Cleveland, OH 44195, USA. finkej@ccf.org
authors.forename: James
authors.initials: J
authors.lastname: Finke
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ko
authors.forename: Brian
authors.initials: B
authors.lastname: Rini
authors.forename: Pat
authors.initials: P
authors.lastname: Rayman
authors.forename: Joanna
authors.initials: J
authors.lastname: Ireland
authors.forename: Peter
authors.initials: P
authors.lastname: Cohen
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis; D039481:CD11b Antigen / Q000096:biosynthesis; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007165:Immunosuppression Therapy; D007211:Indoles / Q000008:administration & dosage*; D007680:Kidney Neoplasms / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis; D011758:Pyrroles / Q000008:administration & dosage*; D000077210:Sunitinib; D047368:Tumor Burden / Q000187:drug effects; D019139:Tumor Escape
chemical_list: D020533:Angiogenesis Inhibitors; D000950:Antigens, Ly; D039481:CD11b Antigen; D007211:Indoles; C480309:Ly6G antigen, mouse; D011758:Pyrroles; D000077210:Sunitinib