Caloric restriction to enhance cancer immunoprevention

About This Grant

Abstract There is great excitement regarding the use of cancer immunoprevention vaccines for patients with elevated cancer predisposition. Lynch syndrome (LS) affects ~1.2 million Americans and predisposes to >70% lifetime colorectal cancer (CRC) risk. LS patients carry CD8+ T cells reactive against MMR deficient rFSPs. Previously, we showed in LS mouse models that vaccination with immunogenic rFSPs increases CD8+ T-cell activation, reduces CRC burden, and prolongs cancer-free survival. Early phase clinical trials show that rFSP vaccination robustly upregulates T-cell immunity in LS patients. LS is thus a paradigm for cancer immunoprevention vaccines. However, vaccine protection is incomplete, and breakthrough CRCs still develop. Thus, new approaches to improve cancer immunoprevention vaccine efficacy and inform clinical trial design are needed. - ------------------------------------------ Energy balance strategies such as caloric restriction associate with reduced CRC risk. A critical aspect of reduced CRC risk with weight loss/energy balance approaches is increased CD8+ T cell-mediated tumor immune surveillance. Memory CD8+ T cells are crucial for anti-tumor immune surveillance and long-term vaccine-induced protection against cancer and pathogens. Our preliminary data shows that caloric restriction enhances the ability of antigen-specific memory CD8+ T cells to protect mice against lethal infections, CRCs and other tumors. Specifically, we show that caloric restriction promotes memory CD8+ T cells to acquire a stem cell memory (Tscm) phenotype. We also show that caloric restriction enhances CD8+ T cell survival, function and mitochondrial metabolism within tumors, all of which are hallmarks of optimal anti-tumor immunity. Our central hypothesis is that caloric restriction will synergize with an rFSP cancer immunoprevention vaccine to boost anti-tumor memory CD8+ Tscm formation, as well as Tscm cell function, survival, mitochondrial metabolism and efficacy to prevent tumorigenesis in Lynch syndrome mouse models.