Biological sex-dependent hormonal signaling and metabolomic profiles in obesity alter tumor microenvironment and immunotherapy outcomes

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Abstract

Commonly viewed as a negative prognostic factor in cancer, obesity is associated with improved responses to cancer immunotherapy using immune checkpoint inhibitors (ICIs). Although data suggest a sexual dimorphism influencing the effects of obesity on immunotherapy responses, to our knowledge, the intersection of sex and obesity on immunotherapy requires further exploration. We demonstrate, in a pan-cancer analysis stratified by sex and BMI, that obesity (BMI ≥ 30) is associated with improved survival after ICI only in male patients. In preclinical models of diet-induced obesity (DIO), we observed that only DIO male tumor-bearing mice responded better to ICI. The differential effect of sex on outcomes was associated with alterations in the tumor microenvironment where DIO female mice demonstrated increased tumor-associated macrophages skewed toward a M2 phenotype. Ovariectomy of DIO female mice reduced M2 polarization and increased anti-tumor immune responses including increases in tumor-infiltrating T cells following ICI. Metabolomic analysis of DIO mice demonstrated distinct profiles base on sex. Re-stratification of female cancer patients revealed that obesity was associated with improved outcome, but only in post-menopausal (age ≥ 55) patients. We identify that the immunotherapy “obesity paradox” is sex-dependent and that hormonal and metabolomic status modulates the influence of obesity on ICIs.

Authors

Logan V. Vick, Spencer R. Rosario, Ziming Wang, Craig Collins, Lam T. Khuat, Yatian Yang, Michael K. Sheng, Wahed A. Firoz, Ryan N. Nielsen, Yao-Hui Sun, Aryana M. Razmara, Hossein Borghaei, Emmanuel S. Antonarakis, Andrew Elliott, Nishant Gandhi, Raid Aljumaily, Sami Ibrahimi, Michael Machiorlatti, Sara K. Vesely, Shuchi Gulati, Sarbajit Mukherjee, Robert J. Canter, Sean J. Judge, Arta M. Monjazeb, William J. Murphy