Abstract P1-04-08: Exosomes from primary breast adipocytes induce immune exhaustion in triple negative breast cancer

Patients with triple negative breast cancer (TNBC), who have co-morbid type 2 diabetes (T2D), have higher risk for metastatic disease and cancer-related mortality. Adipose tissue in T2D is inflamed/dysfunctional and secretes factors that reprogram breast tumor cells. However, adipocyte crosstalk with breast cancer cells is not well understood. Preliminary data suggest this crosstalk promotes immune exhaustion in the tumor microenvironment. It is well established that patients with chronic T2D are ‘immune exhausted’, exhibiting impaired metabolism, reduced effector function, and elevated expression of immune checkpoint proteins on multiple T cell subsets in the periphery and tumor infiltrates. We hypothesized that dysfunctional adipose tissue drives this immune exhaustion in the breast microenvironment, through exosome communication. Recent studies have focused attention on exosomes, which are membrane-enclosed extracellular vesicles (EVs) that contain parent cell-specific biomolecules on the membrane and in the cargo, which are delivered to recipient cells. We tested EVs purified from conditioned media of insulin resistant (IR), primary mature breast adipocytes for their ability to upregulate PD-L1 expression in MDA231 and MCF7 cells, as models of TNBC and ER+ breast cancer. We compared to EVs purified from conditioned media of insulin sensitive (IS), primary mature breast adipocytes as controls. Adipose tissue was obtained surgically with consent from reduction mammaplasty patients without known breast cancer. IR adipocyte EVs upregulated PD-L1 mRNA and protein expression in both cell types, and five times more than IS adipocyte EVs in MCF7 cells. Our laboratory has proven that BET bromodomain proteins regulate transcription of several immune check point genes in TNBC. We found that BET protein inhibition by the pan-BET inhibitor JQ1, and the BRD4-selective PROTAC degrader MZ1, disrupts exosome-driven PD-L1 expression. Network analysis of the exosome-mediated signaling suggests that regulation of immune exhaustion ligands is coupled to epithelial-to-mesenchymal transition and metastatic potential. Understanding the effect of metabolically abnormal breast adipocytes in patients with breast cancer and T2D will help refine prognosis, evaluate responses to immune checkpoint therapies such as atezolizumab, which is approved for PD-L1 positive TNBC, and potentially prevent tumor metastasis. To our knowledge, our study is the first to test the impact of exosomes derived from primary mature breast adipocytes, as a function of insulin sensitivity and patient metabolism, on immune exhaustion in invasive breast cancer. Our findings inform clinical considerations and follow up of breast cancer patients with T2D. These refinements are critical because, at present, breast adipocyte health does not inform the standard of care in breast medical oncology. Our insights should improve treatment for immune dysfunction in T2D cancer patients at risk for tumor progression. 424 words3,004 characters with spaces Citation Format: Naser Jafari, Manohar Kolla, Isabella Pompa, Tova Meshulam, Miguel Batista Junior, Gerald V Denis. Exosomes from primary breast adipocytes induce immune exhaustion in triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-04-08.