VTX-2337, a synthetic small-molecule agonist specific to TLR8 was investigated in two phase II trials in recurrent OC (85, 86). microenvironment in OC in order to develop effective therapies. This review will discuss immune subpopulations in OC microenvironment, Ceftobiprole medocaril current immunotherapy modalities targeting these immune subsets and data from clinical trials screening IO treatments in OC and its combination with other therapeutic brokers. mutated, or homologous recombination deficient OC may harbor higher levels of personal neoantigens presumably due to their defective DNA repair machinery (25). In addition, OC have been reported to demonstrate cancer associated antigens such as NY-ESO-1, mutated p53, Mesothelin, MUC-16, SCP-1which could drive immunogenecity (26). In this review we will discuss the ongoing strategies which are being explored to enhance the antitumor immune response in OC beyond PD-1/PD-L1 inhibition including: (i) combining anti PD-1/PD-L1 brokers with other brokers, and (ii) targeting other relevant immune subsets. Combination Methods Poly (ADP-Ribose) Polymerase (PARP) Inhibitors and ICIs Approximately 25% of high grade serous ovarian malignancy harbor a germline or somatic mutations in the tumor suppressor genes or (27, 28). mutated OC are associated with a higher lymphocyte infiltration (25, 29). BRCA1/2 are involved in DNA damage response the homologous recombination (HR) pathway. HR participates in genome stability by repairing complex DNA damage such as DNA double-stranded breaks. Several studies have Ceftobiprole medocaril highlighted that mutated OC harbor a higher quantity of tumor specific neo-antigenes and demonstrate increased expression of the immune checkpoint Ceftobiprole medocaril modulators, PD-1 and PD-L1, which indicated that mutated OC may be Ceftobiprole medocaril more sensitive to PD-1/PD-L1 inhibitors (25). Regrettably, the JAVELIN 100 trial assessing the efficacy of avelumab (anti-PD-L1) in patients with previously treated recurrent of refractory OC showed that BRCA status was not associated with clinical response (30). Recently, increasing evidence has suggested the importance of the link between DNA damage and innate immunity (31). PARP inhibition in Stimulator of Interferon Genes (STING) pathway activation (32). PARPi induced STING activation occurs mainly in tumor cells. This pathway results in release of interferon related cytokines which in turn increase NK and other cell mediated cell killing upregulation in NKG2D ligand for example. The MEDIOLA trial evaluated the combination of Olaparib (PARPi) and Durvalumab (anti-PD-L1) in mutated platinum-sensitive relapsed OC (33). The objective response rate was high at 71,9% but should be interpreted with caution as this response rate could be expected with a PARPi alone in altered OC. It is therefore difficult to conclude that there was synergistic or even additive benefit to this combination. Combination of PARPi and anti-PD-L1 has also been tested in wild type OC. The combination of the PARPi niraparib and pembrolizumab (anti-PD-1) resulted in an encouraging 25% RR among patients with mainly Ceftobiprole medocaril platinum resistant recurrent OC (34). Anti-Angiogenic Brokers and ICIs Vascular endothelial growth factor (VEGF) is usually a key regulator of physiological and pathological angiogenesis and plays a major role in tumorigenesis (35). VEGF is usually highly expressed in OC microenvironment (36). It promotes tumor angiogenesis, enhances vascular permeability and favors peritoneal dissemination of OC through malignant ascites formation (37). In addition to its contribution to tumor angiogenesis, VEGF also has immunosuppressive properties. VEGF inhibits T-cell function, contributes to the induction and maintenance of regulatory T cells (Tregs), inhibits functional maturation of DC, enhances expression of inhibitory immune checkpoint on CD8+ cells and promotes tumor-associated macrophages (38). Combining anti-angiogenic brokers with ICIs could reverse immunosuppression mediated by VEGF and thus increase the efficacy of ICIs in OC. the secretion of TGF-, which downregulate the expression of MHC II and co-stimulatory molecules on DC. CAFs can secrete IL-6 and thereby contribute to monocytes recruitment Rabbit Polyclonal to CDK8 and macrophages differentiation to M2-like phenotype. TGF- expression by CAFs negatively regulate NK cells activation and cytotoxic activity. FAPhigh CAFs increase differentiation of CD4? cells into CD25+FoxP3+ Tregs and retain them at their surface by expression of OX-40. Tregs constitutively express the co-inhibitory molecule, CTLA-4 which inhibits antigen presentation by binding on CD80 and CD86, co-stimulatory molecules expresses on DC. Tregs also inhibit CD8+ LT activation IL-2 consumption which is necessary to T-cells activation. The cytokine CCL22 produces by TAMs generate chemokine gradient that induces Treg accumulation in the TME. TAMs also express co-inhibitory molecules such as PD-L1 or B7-1/B7-2 and suppress CD8+ LT cytotoxic activity upon activation with their ligand, PD-1 and CTLA-4. TAMs also impair LT activity though metabolization of L-Arginine.