Abstract SY38-01: Diverse effects of obesity on cancer immunology and therapy: Both the good and the bad

Abstract Obesity (BMI of 30 or higher) has reached pandemic proportions in the US and continues to rise. Obesity is associated with increased cancer incidence, progression, and mortality. Obesity is also associated with a meta-inflammation as well as general immune suppression. However, we and others have observed in both preclinical models involving diet-induced obese (DIO) mice as well as clinical cancer outcomes, that obesity can be associated with increased efficacy and T cell responses following immune checkpoint inhibition (ICI) targeting PD-1/PDL-1 (Wang Z et al, Nat Med 2019). This protective effect in preclinical models occurred despite marked increased tumor growth and progression in DIO mice. The results indicated that an “obesity paradox” existed regarding some cancer immune therapies. However, this increased efficacy did not apply to all immune therapy responses as we have also observed that following strong systemic immunostimulatory regimens such as with high dose cytokines (IL2) or following an allogeneic hematopoietic stem cell transplant (HSCT), that obesity was correlated with poorer outcomes due to increased cytokine release syndrome (CRS) due to macrophage dysregulation, reduction in gut microbiome diversity, and increased gut permeability, in both preclinical models and clinical outcomes (Khuat LT et al, Sci Trans Med 2020). These results indicated that a balance exists between the positive and negative effects of obesity which could be contingent on the particular type of cancer immunotherapy applied. With ICI, obesity is beneficial, but strong systemic immunostimulatory therapies can result in heightened proinflammatory responses and pathologies. It has also been reported that sex differences regarding the obesity paradox may also occur with high BMI males demonstrating increased anti-tumor efficacy (McQuade JL et al, Lancet Oncol 2018). The physiology of obesity regarding adiposity deposition and metabolic perturbations are also affected by sex hormones and obesity can also have marked effects on both androgen and estrogen production. We therefore assessed the role of sex on different cancer immunotherapy outcomes in obesity. Following systemic cytokine application or after allogeneic HSCT, no differences were observed between male and female DIO mice regarding the increased toxicities due to CRS. In marked contrast, following ICI targeting PD-1, increased anti-tumor effects were only observed in male and not female DIO mice. This was associated with immune differences in which female DIO mice had higher myeloid derived suppressor cells (MDSCs) and decreased T cell responses. However, when female mice were ovariectomized before placed on diet, application of ICI now resulted in increased anti-tumor efficacy comparable to DIO males. Importantly, metabolomics indicated that key metabolite changes could be correlated with the return of responsiveness. Similarly, clinical outcomes stratified on both sex and BMI also demonstrated the increased efficacy following ICI in high BMI males. These results demonstrate that sex-linked differences exist regarding the effects obesity has on cancer immunotherapy outcome following ICI but not other types of immune therapies. Further, these sex-based differences in obesity can be correlated with immunological alterations, and these can be reversed by estrogen inhibition suggesting that hormone modulation may offer immunological benefits in the context of obesity following cancer immunotherapy involving ICI. Citation Format: William J. Murphy, Logan Vick, Robert Canter, Spencer Rosario, Arta Monjazeb. Diverse effects of obesity on cancer immunology and therapy: Both the good and the bad [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY38-01.