Abstract A57: βhCG regulates immune cell population in BRCA1 mutated breast cancers

Abstract

Abstract BRCA1 mutation predisposes to tumors mainly to the breast and ovaries, though the exact reason for the said tissue specificity still remains a mystery. We have shown that when breast cancer cells become defective in BRCA1, hCG is overexpressed. Also, we have demonstrated that β-hCG can promote tumor progression by inducing TGFβRII, specifically and selectively in BRCA1 defective breast cancer cells in vitro (Sengodan et al., 2017). β-hCG induces expression of hemoglobin genes and protects the cancer cells during oxidative stress, resulting in drug resistance (Sengodan et al., 2017). Since hCG has immunosuppressive action, we hypothesized that hCG might be skewing the immune response of the BRCA1 defective cells towards tumorigenesis. To examine the immunologic response of βhCG in vivo, we performed studies using NOD-SCID and Balb/C mouse models by orthotopically implanting BRCA1 wild-type, BRCA1 mutated, and βhCG overexpressed BRCA1 mutated breast cancer cells in to the fourth mammary fat pad of the mice. We used flow cytometry to characterize immune cell populations in lymphoid tissues and infiltrating the tumor. Myeloid-derived suppressor cells (MDSC), which promote tumor growth by inhibiting T-cell immunity, M1 and M2 macrophages, which are involved in antitumorigenic and protumorigenic immune responses respectively, CD4/CD8 T cells, and FoxP3 T regulatory cells, which play an important role in T cell-mediated immune response, were analyzed. Comparison of MDSC from spleen and tumor done in various studies has demonstrated that tumor MDSC have more potent suppressive activity than that from other peripheral lymphoid organs (Maenhout et al., 2013; Corzo et al., 2018). In our study there was a significant increase in the percentage of tumor MDSCs and M2 macrophages in the order, BRCA1 wild-type < BRCA1 mutant < βhCG overexpressed BRCA1 mutant breast cancers. Correspondingly, there was a significant decrease in CD8+/FOXP3+ ratio in the order, in the tumors derived from mouse models that received BRCA1 wild-type < BRCA1 mutated < βhCG overexpressed BRCA1 mutated cancers. This reflects a marked decrease in the proportion of tumor-infiltrating cytotoxic CD8+ T cells, coincident with an increase in the proportion of FOXP3+ Treg cells, which adds to the suppressive action of βhCG in BRCA1 mutated breast cancers. Collectively, these findings raise the possibility that induction of βhCG found in BRCA1-mutated tumors increases the population of MDSC and M2 macrophages, thus inhibiting the host antitumor immune response and promoting tumor growth. It was also proved for the first time in our study that βhCG causes a decrease in the proportion of cytotoxic CD8+ T cells in BRCA1 mutant cancer cells. This study shows that resistance to immunotherapy shown by BRCA1 mutated breast cancers could be reverted by modulating βhCG in BRCA1-defective cancer patients. Citation Format: Geetu Rose Varghese, Vishnu Sunil Jaikumar, Arathi Rajan, Neetha Rajan Latha, Dipyaman Patra, Priya Srinivas. βhCG regulates immune cell population in BRCA1 mutated breast cancers [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A57.