Immunotherapy as a treatment for cancer is a growing field of

Immunotherapy as a treatment for cancer is a growing field of endeavor but reports of success have been limited for epithelial ovarian cancer. CD8+ T-cell responses in preliminary clinical trials following vaccination, but often in the absence of clinical responses. This is perhaps due to widespread immunosuppression in the TME preventing T-cell activation and proliferation, as well as tumor heterogeneity and immunogenicity that impede proper TAA presentation to the immune cells. The EOC immunopeptidome was profiled by isolating HLA molecules primarily from HGSC tumors and which were analyzed by mass spectrometry [57]. The analysis identified relevant proteins including CRABP1/2, FOLR1, and KLK10 presented on major histocompatibility complex (MHC) I molecules, and mesothelin, PTPRS and UBB presented on MHC-II molecules [57]. The most abundantly detected protein presented on MHC-I molecules was MUC16 (CA-125), with 113 different peptides expressed in approximately 80% of patients. MUC16-derived peptides were highly immunogenic (85% T-cell responses in vitro), and consequently it was proposed as the top candidate for targeted immunotherapy moving forward [57]. Although CA-125 is usually immunogenic, the large number of trials with a monoclonal antibody Fustel novel inhibtior targeting CA-125 (Table 3) have been mostly unsuccessful as a monotherapy [76]. This failure could be explained by the weak magnitude of the immune response generated, the loss of expression or down-regulation of CA-125 on EOC cells to avoid immune recognition, or the overgrowth of CA-125(-) EOC cells as a consequence of cancer immunoediting process. A single TAA is generally only expressed in a subset of patients, making the design of a universal immunotherapy challenging. The main barrier of targeting a single TAA is cancer immunoediting, which enables the enrichment of neoplastic cells in tumors that do not express the targeted TAA over time. Chimeric antigen receptor T (CAR-T) cells provides the option of combining multiple antigen specificities, and delivering direct cytokine stimulation (GM-CSF, IL-12) to the TME, irrespective of the MHC status of the patient [8]. 2.4. Tumor Immunogenicity and Other Immunoinhibitory Molecules Loss of immunogenicity is an immune hallmark of cancer that is exploited Fustel novel inhibtior by tumors to evade immune recognition. This can be brought on by down-regulation or loss of Fustel novel inhibtior expression of MHC-I and -II, and the antigen processing and presentation machinery (APM) [77,78,79,80]. Expression of MHC-I genes is usually altered by 60C90%, depending on the cancer type. These impairments reduce the antigens presented around the cell surface leading to decreased or lack of recognition and elimination by cytotoxic T lymphocytes. The mechanisms that are related to immune cell infiltration in EOC are dependent on MHC-I and -II status [3,81]. The presence of neoantigen-reactive T cells in patients with EOC can improve survival [82]. However, as mentioned before, since ovarian tumors possess intermediate/low mutation burdens, the incidence of naturally processed and presented neoantigens generating a significant antitumoral response is very low [13]. The expression of APM components Fustel novel inhibtior and the presence of intratumoral T-cell infiltrates were significantly associated with improved survival [81]. Han. et al. exhibited that the majority of ovarian carcinomas analyzed had either heterogeneous or positive expression of peptide transporter 1 (TAP1), TAP2, HLA class I heavy chain, and beta-2 microglobulin [81]. Concurrent expression of HLA-DR and CA-125 on cancer cells correlated with higher frequency of CD8+ TILs and increased survival [83]. Similarly, tumor cell expression of HLA-DMB was associated with increased numbers of CD8+ TILs and both were associated with improved survival in advanced-stage serous EOC [84]. The regulation of APM components and MHC molecules in human cancers is a significant area of research but is usually beyond the scope of this review (reviewed in [85,86]). The mutational profile of EOC can also predict immunogenicity. Tumors with deficient homologous recombination (HR) machinery occur with a frequency of up to 50% [33]. These include mutations in (20% frequency) or non-BRCA HR deficiencies (Fanconi anemia genes, restriction site associated DNA genes, and DNA damage response genes) [33]. HR deficient tumors have higher predicted neoantigen load, and infiltrating and peritumoral lymphocytes HDACA in these tumors have increased PD-1/PD-L1 expression [43], which may enhance susceptibility to immune checkpoint therapy. mutated HGSC tumors have more CD3+ and CD8+ TILs compared to HR-proficient tumors, a signature associated with higher overall survival [43,87]. p53 mutations are also associated with higher levels of TILs [87,88]. Non-HR deficient tumors therefore have poorer overall survival [43] and may be less immunogenic, making them more difficult to target with immunotherapies. Alternative strategies and TAAs to target this group of EOC tumors need further investigation. The expression of immunoinhibitory molecules on cancer cells, including PD-L1 and Indoleamine 2,3-dioxygenase (IDO) are associated with patient prognosis. Higher expression of PD-L1 on tumor cells correlates.