Inflammatory Drivers of The Obesity-Cancer Connection

Endeavor Award (2023-Present)

Vanderbilt University: Jeffrey Rathmell, PhD; Alyssa Hasty, PhD • The University of Pennsylvania: Kathryn Wellen, PhD • University of Tennessee Health Sciences Center: Liza Makowski, PhD

Jeffrey Rathmell, PhD

Alyssa Hasty, PhD

Kathryn Wellen, PhD

Liza Makowski, PhD

Obesity is a growing health concern and represents a significant risk factor for developing at least 13 different cancer types. Interestingly, however, is the observation of the “obesity paradox,” where once diagnosed, obese cancer patients may respond better to immune checkpoint therapies. Multiple mechanisms have been put forward to explain the simultaneous increased risk for both cancer development and increased potential for therapeutic response in obese individuals. However, while there are several hypotheses regarding the interplay between obesity, immune reshaping, and cancer risk, there is still limited understanding of how obesity affects immune cells within tumors. A lack of matched tumor and adipose tissue from the same patients, consideration of the source and type of adipose tissue being considered, and oversimplification of obesity to single metrics such as BMI has muddled the field. Now, to address these questions, this Endeavor team with expertise in cancer biology, immune metabolism, adipose tissue biology, and obesity, will embark on a program of integrated mechanistic research projects to discover how obesity reshapes immunity to support cancer growth while potentially sensitizing to immunotherapies.

By directly comparing tumor and adipose tissues, the research team aims to identify shared and unique features of obesity-associated inflammation in different cancer types. The research plan rests on the foundation of establishing shared sample and analysis cores for patient-matched tumor and adipose samples. These cores will serve as a shared resource among four interconnected projects, and this standardization will be crucial for data harmonization across the studies. These studies will explore the mechanisms that drive the inflammatory features of the obesity-cancer connection and how these may influence tumor progression and responses to immunotherapy.  The team will focus on three types of obesity-associated cancers: renal, pancreatic, and colorectal cancers. The projects will investigate the role of macrophage PD-1, the impact of weight cycling on immune cell populations, the metabolic signaling in adipose-tumor communication, and the changes in systemic inflammation and tumor microbiome induced by obesity.

Overall, the team seeks to uncover novel insights into the complex interplay between obesity, the immune system, and cancer. Obesity is at epidemic levels and continues to increase both in the US and globally. The diversity of cancer types for which obesity increases risk and the potential for increased immunotherapy responses makes this a crucial area for exploration. The research findings could lead to new therapeutic strategies to target obesity-associated cancer growth and enhance the effectiveness of immunotherapies, with mechanistic insights and therapeutic targets that can ultimately be used to improve cancer care for both obese and non-obese patients.