Impact of Salt Modified Diet on Systemic IRAE in Breast Cancer Immunotherapy
Abstract
Breast cancer is the most common type of cancers in women worldwide and is one of the leading causes of cancer-related mortality in women in the United States. Over the past few decades, cancer immunotherapy has emerged as a promising treatment for different types of cancers. Immune checkpoint inhibitors (ICI) is a class of immunotherapy that has proven to be effective against breast cancer, as shown by data from various clinical trials with monoclonal antibodies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death1 (PD-1), and programmed death ligand-1 (PD-L1). However, development of unpredictable immune-related adverse events (irAEs) following ICI therapy poses a challenge to its clinical benefits. Previous research in our laboratory and others have shown that high-salt (HS) plays a role in inflammatory activation of CD4+T cells, thereby leading to anti-tumor responses. The goal of this study is to evaluate the impact of dietary salt modification on therapeutic and systemic outcomes in breast-tumor-bearing mice, subsequent to anti-CTLA4 monoclonal antibody (mAb) based ICI therapy. As both HS diet and ICI are associated with activation of CD4+T cells, we hypothesized that a combination of these two factors would induce enhanced irAE response. Murine breast tumor models were developed by injecting Py230 murine breast cancer cells into mammary fat pad of 12 week old C57Bl/6 mice. The tumor-bearing mice were divided into three cohorts to study the impact of dietary salt modification- mice on normal-salt (NS) diet; mice on high-salt (HS) diet; and mice on low-salt (LS) diet. Next, to investigate the effect of salt-modified diet on anti-tumor efficiency of anti-CTLA4 mAb based ICI therapy, the mice were injected with monoclonal antibodies on day 7, 10, and 13. The results indicated that HS diet cohort with anti-CTLA4 showed the worst survival outcome, out of the three cohorts. Also, the combination of high-salt and anti-CTLA4 mAbs exhibited increased lung infiltration and circulating levels of inflammatory cytokines than LS diet cohort. With anti-CTLA4 mAbs, LS diet cohort on the other hand had enhanced survival advantage compared with NS diet cohort in combination with anti-CTLA4 mAbs, and reduced tumor progression than isotype mAb. In conclusion, the data from our study suggests that LS diet not only reduced irAE response in breast cancer based- murine models when treated with anti-CTLA4 mAbs, but also retained the immunotherapeutic efficacy of anti-CTLA4 mAbs against cancer.
Subject Area
Oncology|Cellular biology|Immunology|Biology
Recommended Citation
Durga Khandekar,
"Impact of Salt Modified Diet on Systemic IRAE in Breast Cancer Immunotherapy"
(2023).
ETD Collection for Tennessee State University.
Paper AAI30315532.
https://digitalscholarship.tnstate.edu/dissertations/AAI30315532