Manipulating the immune environment with immune checkpoint inhibitors (ICIs) could therefore represent an attractive strategy. Overall, the immune TME (tumor microenvironment) may be relevant in OC, a high infiltration by effector CD8 T cells may contribute to survival in some patients with OC. 18 The authors also found that the density of intraepithelial CD8+ T cells was inversely correlated to the expression of PD-L1, suggesting that the expression of PD-L1 on tumor cells may result in CD8+ T-cell exclusion. An early study found that almost two thirds of ovarian tumors demonstrated low level PD-L1 expression, mainly on immune cells rather than tumor cells, and that expression of PD-L1 was associated with significantly worst prognosis. The PD1 receptor can be expressed on CD8+ and CD4+ T cells (including Tregs), whereas PD-L1 is expressed on activated T cells, tumor-infiltrating macrophages or fibroblasts and cancer cells. 17 In fact programmed death-1 (PD1) and its ligand PD-L1 are probably the best described immune co-inhibitory molecules. For example, OC cells frequently over-express CD47, a ‘don’t eat me’ signal that allows them to escape phagocytosis by innate immune cells, 16 while lymphocytes or myeloid DCs in ovarian tumor tissue and draining lymph nodes often express the inhibitory molecule programmed cell death ligand-1 (PD-L1). 15 Finally, upregulation of inhibitory receptors in tumor or immune cells may further promote immune tolerance in OC. 12 – 14 In addition, the recruitment of immunosuppressive M2 polarized tumor-associated macrophages or immature dendritic cells (DCs) further contribute to an immunosuppressive tumor microenvironement. For example, regulatory T cells (Tregs), identified by their combined expression of CD4, CD25 and intracellular forkhead box P3 (FOXP3), have the capacity to inhibit the activity of immune cells through cytokines such as transforming growth factor beta (TGF-β) and interleukin (IL)-10 and induce an immunosuppressive phenotype in other cells such as macrophages thereby limiting anti-tumor immunity and favoring malignant cell growth. 10, 11 In addition, a vast network of immune inhibitory processes balance and counteract the cytotoxic function of T cells. Not surprisingly, down-regulation in certain major histocompatibility complexes (MHC) results in decreased TIL density and reduced survival in advanced OC. A functional antigen processing machinery has been shown to influence CD8+ and or CD3+ immune cell recruitment and activation. However, to be effective, an anti-tumor immune response requires a sequence of tightly orchestrated interactions. 9 Taken together these data suggest that the OC microenvironment could have an impact on prognosis and/or response to treatment.
8, 9 In particular, the most recent and largest meta-analysis including 21 studies and almost 3000 patients with OC confirmed that high levels of intra-epithelial CD3+ or CD8+ T cells were most strongly associated with both improved progression-free survival (PFS) and overall survival (OS). 4 – 7 Most importantly, high TILs have been consistently and reproducibly associated with survival. 2, 3 Humoral or cellular immunity against TAAs has been demonstrated in patients with OC including antibodies or T-cell subsets against oncogenic p53, NY-ESO-1 or LAGE-1. 1 These oligoclonal TILs recognize tumor-associated antigens (TAAs) and can generate autologous tumor cell-specific cytotoxicity in vitro. Tumor infiltrating lymphocytes (TILs) can be detected in half of OC tumors at diagnosis. Background and rationale for targeting immune checkpoints in epithelial ovarian cancerĪ number of studies over the past two decades have suggested that ovarian cancers (OCs) are immunogenic and capable of stimulating host anti-tumor immune responses.