Obesity triggers tumoral senescence and renders poorly immunogenic malignancies amenable to senolysis
Frédérik Fournier, Roberto Diaz-Marin, Frédérique Pilon, Mathieu Neault, Rachel Juneau, Gabrielle Girouard, Ariel M. Wilson, Bruno Larrivée, Frédérick A. Mallette, Sergio Crespo‐Garcia, Przemysław Sapieha
Abstract
Obesity is a major risk factor for cancer. Conventional thought suggests that elevated adiposity predisposes to heightened inflammatory stress and potentiates tumor growth, yet underlying mechanisms remain ill-defined. Here, we show that tumors from patients with a body mass index >35 carry a high burden of senescent cells. In mouse syngeneic tumor models, we correlated a pronounced accretion of senescent cancer cells with poorly immunogenic tumors when mice were subjected to diet-induced obesity (DIO). Highly immunogenic tumors showed lesser senescence burden suggesting immune-mediated elimination of senescent cancer cells, likely targeted as a consequence of their senescence-associated secretory phenotype. Treatment with the senolytic BH3 mimetic small molecule inhibitor ABT-263 selectively stalled tumor growth in mice with DIO to rates comparable to regular diet-fed mice. Thus, consideration of body adiposity in the selection of cancer therapy may be a critical determinant for disease outcome in poorly immunogenic malignancies.