Targeting myeloid cells in the tumor microenvironment enhances vaccine efficacy in murine epithelial ovarian cancer

Abstract

Epithelial ovarian cancer (EOC) is typically diagnosed at advanced stages, and is associated with a high relapse rate. Patients in remission are ideal candidates for immunotherapy aimed at cure or prolonging disease-free periods. However, immunosuppressive pathways in the tumor microenvironment are obstacles to durable anti-tumor immunity. In a metastatic syngeneic mouse model of EOC, immunosuppressive macrophages and myeloid-derived suppressor cells (MDSCs) accumulate in the local tumor environment. In addition, resident peritoneal macrophages from non-tumor-bearing mice were highly immunosuppressive, abrogating stimulated T cell proliferation in a cell contact-dependent manner. Immunization with microparticles containing TLR9 and NOD-2 ligands (MIS416) significantly prolonged survival in tumor-bearing mice. The strategy of MIS416 immunization followed by anti-CD11b administration further delayed tumor progression, thereby establishing the proof of principle that myeloid depletion can enhance vaccine efficacy. In patients with advanced EOC, ascites analysis showed substantial heterogeneity in the relative proportions of myeloid subsets and their immunosuppressive properties. Together, these findings point to immunosuppressive myeloid cells in the EOC microenvironment as targets to enhance vaccination. Further studies of myeloid cell accumulation and functional phenotypes in the EOC microenvironment may identify patients who are likely to benefit from vaccination combined with approaches that deplete tumor-associated myeloid cells.

IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer

“…Myeloid derived suppressor cells (MDSCs) are a subset of such suppressive cells that have been shown to play a major role in immune suppression in the ovarian cancer microenvironment (31). In a murine model of breast cancer, we have shown that a combination regimen of peptide vaccine (MHC Class I binding immunogenic peptides from rat neu (neu), legumain and β-catenin targeting tumor cells, cancer stem cells, and tumor associated macrophages) and PD-1 blocking antibody leads to a decrease in the frequency of MDSCs in the tumor (22, 32).…”

Cytokine profiling of ascites at primary surgery identifies an interaction of tumor necrosis factor-α and interleukin-6 in predicting reduced progression-free survival in epithelial ovarian cancer

“…The critical role of immune surveillance in EOC was demonstrated by correlation of survival with tumor-infiltrating lymphocytes (TILs) [5]. However, the tumor microenvironment in EOC is inflammatory, characterized by myeloid cell accumulation and expression of pro-inflammatory cytokines and chemokines, while also being immunosuppressive [6-10]. Ascites from patients with EOC inhibited T cell receptor-induced NF-kB and NFAT signaling in tumor-associated T cells [6].…”

“…Accumulation of H4-expressing macrophages in the tumor environment can impede T cell responses and correlate with more rapid tumor recurrence in EOC [13, 14]. Myeloid-derived suppressor cells (MDSCs) also accumulate in the ascites of patients with advanced EOC [7, 10]. In addition to being obstacles to antitumor immunity, tumor-infiltrating myeloid cells can release matrix metalloproteinases and pro-angiogenic factors (e.g., vascular endothelial growth factor) as part of a wound repair response that can promote tumor invasion and spread [15].…”

Biological markers of prognosis, response to therapy and outcome in ovarian carcinoma

“…MDSC accumulate in OvCa, inhibit T cells responses and correlate with more rapid recurrence in OvCa patients [67,68]. Obermajer et al showed that MDSC accumulated in the ascites of patients with advanced OvCa, and that they suppressed T cell proliferation ex vivo [69].…”