Abstract 3866: Investigating tumor infiltrating immune cells signature in obese triple negative breast cancer
Authors: Hossain Fokhrul , Ucar Deniz A , Sanchez-Pino Maria , Dean Matthew , Majumder Samarpan , Wyczechowska Dorota , Monticone Giulia , Sabol Rachel , Xu Keli , Valle Luis D , Zabaleta Jovanny , Bunnell Bruce , Miele Lucio 
Published: September 2020

Triple negative breast cancer (TNBC) is a heterogeneous group of clinically aggressive breast cancers and TNBC patients are pathologically negative for estrogen receptor (ER−), progesterone receptor (PR−), and human epidermal growth factor receptor 2 (HER2−) amplification, which impedes the use of targeted therapies used in other breast cancer subtypes. Obesity is a chronic state of inflammation and is associated with increased secretion of pro-inflammatory cytokines, increased infiltration of immune cells and the development of a microenvironment that supports tumor growth. Several epidemiological studies support the association of obesity with TNBC; however, the underlining molecular mechanisms remain unknown. We developed an immunocompetent obese FVB (female) mouse model by feeding ‘Western diet' or control diet for four months and then injecting with syngeneic C0321 (mouse TNBC) cells to investigate the immune signatures and to study the role of obesity related factors in TNBC progression. We found significant body weight increases in ‘Western diet' fed mice group as expected. The percentage of CD8+ and CD4+ T cells, and macrophages in spleen, liver and peripheral blood in obese mice did not change significantly compared to lean mice. However, the percentages of immunosuppressive Myeloid Derived Suppressor cells (MDSCs), particularly Monocytic-MDSCs were elevated in liver and visceral fat tissue in obese mice. Importantly, tumors in ‘Western Diet' fed mice achieved significantly larger volumes. We found no noticeable difference in the percentage of CD8+ and CD4+ T cells, MDSC or macrophages in the spleen of tumor bearing obese mice. Interestingly, there was a decreasing trend in tumor infiltrating CD8+ and CD4+ T cells in tumor bearing obese mice. Further, tumor infiltrating myeloid cells, MDSCs and macrophages were significantly increased in obese mice, suggesting the formation of an immunosuppressive environment. More importantly, tumor infiltrating MDSCs from obese mice were more immunosuppressive than those from lean mice. In summary, our results reveal alterations in the number and function of tumor infiltrating immune cells in obese mice. RNA-Sequencing of lean vs obese tumors revealed significant changes in pathways related to Hypertrophic and Dilated Cardiomyopathy, Adrenergic signaling in Cardiomyocytes, as well as signaling pathways of Insulin, cGMP-PKG, Glucagon, Calcium and Adipocytokine and others. Our data warrants further investigation on the immunosuppressive tumor microenvironment in obese TNBC patients.

Citation Format: Fokhrul Hossain, Deniz A Ucar, Maria Sanchez-Pino, Matthew Dean, Samarpan Majumder, Dorota Wyczechowska, Giulia Monticone, Rachel Sabol, Keli Xu, Luis D Valle, Jovanny Zabaleta, Bruce Bunnell, Lucio Miele. Investigating tumor infiltrating immune cells signature in obese triple negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3866.