Elise Alspach, PhD, CRI CLIP Investigator

In this proposal, Dr. Alspach investigates the relationship between obesity, sex, and the efficacy of immune checkpoint therapy (ICT) in cancer. Despite the general immunosuppression and higher cancer risk seen in obesity, obese patients often show improved responses to ICT. However, the apparent benefit of obesity to ICT response shows a striking sex difference, with obese male patients responding better to ICT than their lean counterparts.

The same benefit is not seen in female patients. This immunotherapy obesity paradox, and its sex differences, lackna clear biologic explanation. Cancer immunoediting is the process by which CD8+ T cells eliminate tumor cells expressing highly immunogenic antigens while also applying selective pressure for less immunogenic tumor cells to escape immune surveillance. Importantly, the level of residual immunogenicity remaining after tumor immune escape is a factor in ICT response. Dr. Alspach’s preliminary studies indicate that tumors from obese mice are more immunogenic than tumors from lean mice, suggesting that obesity may dampen immunoediting and result in the development of tumors with greater immunogenicity and potential to respond to ICT.

Interestingly, obese females exhibit stronger anti-tumor CD8+ T cell responses than males. Dr. Alspach hypothesizes that obesity’s suppression of anti-tumor immunity is more pronounced during tumor evolution in males than in females, resulting in sex-based differences in immunoediting that explain the obesity paradox disparity observed between the sexes. Dr. Alspach’s research aims to move clinical discoveries to the laboratory, and laboratory discoveries back to the clinic, to refine immunotherapy approaches that incorporate patient sex and body composition as critical factors in
therapy optimization.

Projects and Grants

Cancer immunoediting as a driver of sex differences in the immunotherapy obesity paradox

Saint Louis University School of Medicine | All Cancers | 2024