Abstract B02: Estrogens regulate tumor associated tissue eosinophilia to promote tumor growth

Abstract

Abstract Increased tumor associated tissue eosinophilia (TATE) is associated with better prognosis in colorectal cancers, melanoma, and prostate cancer, however, the mechanisms which regulate TATE and how it impacts tumor biology remain largely unexplored. Eosinophils within tumors have been shown to secrete cytotoxic granular contents that induce necrosis and lead to the recruitment of other immune cells which together inhibit tumor growth. Interestingly, estrogens have been shown to increase eosinophilia in several disease settings although it has not been established if and how estrogens impact eosinophilia in various cancers. Thus, we have explored the role of estrogens in regulating TATE, and its impact on tumor progression, in preclinical models of breast cancer and melanoma. To this end eight weeks old female C57BL6 mice were ovariectomized and supplemented with either placebo or 17β-estradiol (E2) (clamping E2 levels) before tumor implantation. In this manner it was determined that E2 accelerated tumor growth in multiple models of TNBC (triple-negative breast cancer) and melanoma and that this was associated with a significant decrease in TATE. Eosinophil depletion studies were performed the results of which confirmed a role for these immune cells in suppressing tumor growth in these disease relevant models. Mechanistically, it was determined that E2 treatment decreased the levels of cytokines that facilitate eosinophil migration and survival in tumors. The direct effects of E2 on eosinophil recruitment into tumors was confirmed using adoptively transferred eosinophils. Moreover, E2 decreased the survival and cytotoxicity of eosinophils differentiated from bone-marrow progenitors. Altogether, these data indicated that E2 has direct and indirect effects on eosinophils wherein they affect eosinophil differentiation in bone marrow as well as modulate the tumor microenvironment resulting in decreased TATE resulting in increased tumor growth. Analysis of the Metabric and TCGA databases revealed a survival advantage for patients with TNBC whose tumors exhibit a higher expression of an eosinophil signature. Importantly, a selective estrogen receptor modulator (SERM), lasofoxifene, a drug which is in late-stage clinical development for metastatic breast cancer, antagonized E2 actions and reversed the negative impact of E2 on TATE and reduced tumor growth. Given the widespread use of SERMs and other endocrine therapies in the treatment of estrogen receptor positive breast cancer, our findings may inform new therapeutic strategies that exploit eosinophil-mediated antitumor response for the treatment of breast cancer and other cancers where the presence of TATE is beneficial. Citation Format: Sandeep Artham, Aditi Goyal, Jovita Byemerwa, Ching-Yi Chang, Donald Patrick Mcdonnell. Estrogens regulate tumor associated tissue eosinophilia to promote tumor growth [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B02.