Low-grade serous ovarian carcinoma (LGSOC) accounts for a relatively large percentage of epithelial ovarian cancers in young women. Although LGSOC is considered to be an indolent cancer, with an estimated median overall survival of 80 months, an updated analysis of 350 women with LGSOC from our Low-Grade Serous Tumor Database indicated that over 85% developed recurrent disease, and almost all ultimately died of the disease. The overall response rate of recurrent LGSOC to various chemotherapy drugs is dismal - less than 4%. To explore the potential of immunotherapy in low-grade serous ovarian carcinoma, we investigate the immune profiles in low-grade serous ovarian carcinoma. In this study, we have generated gene expression profiles from microdissected epithelial tumor cells and the corresponding LGSOC bulk tumors. Such a novel comparison revealed an immune active tumor stromal microenvironment with highly expressed genes involved in immune response, antigen processing and presentation. The down-regulation of MHC-I gene expression or antigen-processing components of the MHC-I pathway in the tumor cells may lead to an escape from immune surveillance. A recent study has indicated that activation of the MAPK pathway in melanoma cancer cells could lead to internalization of MHC-I and subsequent sequestration within endolysosomal compartments. This sequestration may diminish antigen presentation and CD8+ T-cell recognition of tumor cells. This is further supported by our immunostaining analysis of CD8+ cells in LGSOC. The data indicated that the majority of LGSOC has less than five intratumoral CD8+ T-cells per high-power field, which is much less than the number of CD8+ T-cells observed in high-grade ovarian serous carcinoma. Thus, this low-number of intratumoral CD8+ cells and low level of MHC-I complex in LGSOC tumor cells would suggest a compromised antigen processing and presentation system. Furthermore, we also compared the number of CD45+ cells in LGSOC with or without BRAF/KRAS mutations. CD45 antigen (leukocyte common antigen) is a unique and ubiquitous membrane glycoprotein expressed on almost all hematopoietic cells, from which CD4+ helper T-lymphocyte, CD8+ cytotoxic T-lymphocyte and other lymphocytes are derived. Our data indicate that LGSOC with BRAF or KRAS mutant proteins had a high number of infiltrating CD45+ hematopoietic cells, which would suggest BRAF or KRAS mutant proteins are immunogenic and would partly explain our observation that patients with LGSOC carrying BRAF or KRAS mutation had longer overall survival. However, there were only a few or no CD8+ T-lymphocytes in the corresponding samples stained with CD45+ cells. In summary, our data suggest that an immune suppressive environment related to MAPK activation exists in LOSOC, which may prevent antigen presentation, maturation and activation of infiltrating cytotoxic T-cells.
Citation Format: Kwong-Kwok Wong, David M. Gershenson. Immunosuppressive microenvironment in low-grade serous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 135.