Abstract 4850: High salt diet induced tumor initiating stem cells mediate breast cancer progression

Abstract

Abstract High-salt (sodium chloride) diets have been associated with several chronic inflammatory diseases. While the role of chronic inflammation in cancer is well established, the specific role of high salt diet in carcinogenesis is unknown. Previous studies with syngeneic murine breast cancer models, both in our laboratory and others, have shown that high salt (HS) diet induced tumor regression through inflammatory activation of anti-tumor adaptive immune responses. We tested this counter-intuitive and suspiciously beneficial role of HS diet by performing sequential passage studies in preclinical murine models. Six week old mice were placed on high salt diet for 2 weeks prior to injection with syngeneic 4T1 and Py230 triple negative breast cancer cells (into BALB/c and C57Bl/6J mice, respectively, referred to as passage-1). Tumors were harvested after four weeks of injection. The cancer cells depleted of immune cells were collected from these harvested tumors and reinjected into new non-tumor bearing mice. This cycle was repeated three times. In passage-1 cohort, by day 28, HS diet induced reduced tumor progression in both 4T1-BALB/c (267 ± 59 mm3) and Py230-C57Bl/6J (238 ± 54 mm3) as compared to regular salt (RS) diet cohort (611 ± 94 mm3 and 473 ± 69 mm3, respectively; p<0.05 for both). However, in passage-4 cohort, by day 28, HS diet induced significantly higher tumor progression in both 4T1-BALB/c (806 ± 91 mm3) and Py230-C57Bl/6J (743 ± 81 mm3) models, as compared to regular salt (RS) diet cohort (577 ± 83 mm3 and 462 ± 77 mm3, respectively; p<0.05 for both). Cellular analysis by flow cytometry revealed that there was a 12-19 fold increase in tumor initiating stems cells (TISCs) in passage-4 HS diet cohort compared to RS diet cohort. Mechanistic studies have demonstrated that there was increased TGFβ expression on TISCs obtained from passage-4 HS diet cohort which correlated with enhanced exhaustion phenotype (CTLA4+) of tumor infiltrating adaptive immune cells (CD4 and CD8 T cells) in this cohort. Co-treatment with anti-TGFβ and anti-CTLA4 monoclonal antibodies (mAb) in passage-4 HS diet cohort, significantly reduced tumor progression (p<0.05), as compared to treatment with either mAb alone. Taken together, these data demonstrated that chronic HS diet leads to expansion of TGFβ expressing TISCs leading to host immune exhaustion and tumorigenesis. Importantly, anti-TGFβ mAb exerted a favorable synergistic effect to enhance the anti-tumor efficacy of immune check-point inhibitors. Citation Format: Lisa Tucker, Sonya Reid, Jeffrey C. Rathmell, Venkataswarup Tiriveedhi. High salt diet induced tumor initiating stem cells mediate breast cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4850.