Low-Salt Diet Reduces Anti-CTLA4 Mediated Systemic Immune-Related Adverse Events while Retaining Therapeutic Efficacy against Breast Cancer

• Published in: Biology (Basel, Switzerland) Switzerland), 2022-05, Vol.11 (6), p.810
• Main Authors: Khandekar, Durga, Dahunsi, Debolanle O, Manzanera Esteve, Isaac V, Reid, Sonya, Rathmell, Jeffrey C, Titze, Jens, Tiriveedhi, Venkataswarup
• Format: Article
• Language: English
• Subjects: Adverse events; Breast cancer; cancer biology; CD4 antigen; Cell activation; Cell interactions; Clinical trials; CTLA-4 protein; cytokines; Cytotoxicity; Diet; Experiments; Flow cytometry; IL-1β; Immune checkpoint inhibitors; Immunotherapy; Inflammasomes; Inflammation; Kinases; Laboratory animals; Lungs; Lymphocytes; Lymphocytes T; Metastasis; Monoclonal antibodies; Nutrient deficiency; Pathogens; Proteins; Salt; t-helper cells; Transgenic mice; Tumors; γ-Interferon
• ISSN: 2079-7737; 2079-7737
• DOI: 10.3390/biology11060810

Immune checkpoint inhibitor (ICI) therapy has revolutionized the breast cancer treatment landscape. However, ICI-induced systemic inflammatory immune-related adverse events (irAE) remain a major clinical challenge. Previous studies in our laboratory and others have demonstrated that a high-salt (HS) diet induces inflammatory activation of CD4+T cells leading to anti-tumor responses. In our current communication, we analyzed the impact of dietary salt modification on therapeutic and systemic outcomes in breast-tumor-bearing mice following anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibody (mAb) based ICI therapy. As HS diet and anti-CTLA4 mAb both exert pro-inflammatory activation of CD4+T cells, we hypothesized that a combination of these would lead to enhanced irAE response, while low-salt (LS) diet through blunting peripheral inflammatory action of CD4+T cells would reduce irAE response. We utilized an orthotopic murine breast tumor model by injecting Py230 murine breast cancer cells into syngeneic C57Bl/6 mice. In an LS diet cohort, anti-CTLA4 mAb treatment significantly reduced tumor progression (day 35, 339 ± 121 mm3), as compared to isotype mAb (639 ± 163 mm3, p < 0.05). In an HS diet cohort, treatment with anti-CTLA4 reduced the survival rate (day 80, 2/15) compared to respective normal/regular salt (NS) diet cohort (8/15, p < 0.05). Further, HS plus anti-CTLA4 mAb caused an increased expression of inflammatory cytokines (IFNγ and IL-1β) in lung infiltrating and peripheral circulating CD4+T cells. This inflammatory activation of CD4+T cells in the HS plus anti-CTLA4 cohort was associated with the upregulation of inflammasome complex activity. However, an LS diet did not induce any significant irAE response in breast-tumor-bearing mice upon treatment with anti-CTLA4 mAb, thus suggesting the role of high-salt diet in irAE response. Importantly, CD4-specific knock out of osmosensitive transcription factor NFAT5 using CD4cre/creNFAT5flox/flox transgenic mice caused a downregulation of high-salt-mediated inflammatory activation of CD4+T cells and irAE response. Taken together, our data suggest that LS diet inhibits the anti-CTLA4 mAb-induced irAE response while retaining its anti-tumor efficacy.