Tumor Cell-Intrinsic Immunometabolism and Precision Nutrition in Cancer Immunotherapy

Abstract

<jats:p>One of the greatest challenges in the cancer immunotherapy field is the need to biologically rationalize and broaden the clinical utility of immune checkpoint inhibitors (ICIs). The balance between metabolism and immune response has critical implications for overcoming the major weaknesses of ICIs, including their lack of universality and durability. The last decade has seen tremendous advances in understanding how the immune system’s ability to kill tumor cells requires the conspicuous metabolic specialization of T-cells. We have learned that cancer cell-associated metabolic activities trigger shifts in the abundance of some metabolites with immunosuppressory roles in the tumor microenvironment. Yet very little is known about the tumor cell-intrinsic metabolic traits that control the immune checkpoint contexture in cancer cells. Likewise, we lack a comprehensive understanding of how systemic metabolic perturbations in response to dietary interventions can reprogram the immune checkpoint landscape of tumor cells. We here review state-of-the-art molecular- and functional-level interrogation approaches to uncover how cell-autonomous metabolic traits and diet-mediated changes in nutrient availability and utilization might delineate new cancer cell-intrinsic metabolic dependencies of tumor immunogenicity. We propose that clinical monitoring and in-depth molecular evaluation of the cancer cell-intrinsic metabolic traits involved in primary, adaptive, and acquired resistance to cancer immunotherapy can provide the basis for improvements in therapeutic responses to ICIs. Overall, these approaches might guide the use of metabolic therapeutics and dietary approaches as novel strategies to broaden the spectrum of cancer patients and indications that can be effectively treated with ICI-based cancer immunotherapy.</jats:p>

Effect of Vitamin D3 Supplements on Development of Advanced Cancer

“…13 One theory is that individuals with obesity may have some defect, such as obesity-induced PD-1 expression and T cell exhaustion and dysfunction, that is corrected with immune checkpoint blockade. 14,15 Thus, an intricate balance between adiposity and immunomodulatory or inflammatory mediators may contribute to the differential response to vitamin D 3 . 16 We hypothesize that vitamin D 3 supplementation reduces the incidence of metastatic cancer at diagnosis or lethal cancer and that the risk reduction is most pronounced in individuals with normal weight.…”

Impact of Diets on Response to Immune Checkpoint Inhibitors (ICIs) Therapy against Tumors

“…Established mechanisms include: Loss or alteration of specific antigens or antigenic machinery [ 28 , 29 ]. Tumors can lose major histocompatibility complex (MHC) class I expression or the intracellular machinery required to transport tumor antigens to the tumor surface for T cell recognition [ 30 , 31 , 32 ]. Tumors can promote an immune-tolerant microenvironment by manipulation of cytokines (increased secretion of IL-6, IL-10, and TGF-beta; consumption of IL-2) that encourage infiltration of regulatory T (Treg) cells, myeloid-derived suppressor cells (MDSCs), and other cell types that inhibit cytotoxic T cell function [ 31 , 33 ].…”

New Immunometabolic Strategy Based on Cell Type-Specific Metabolic Reprogramming in the Tumor Immune Microenvironment

“…This review discusses how immune cell functions are determined [ 9 ] by immune cell type-specific metabolism, which is related to the competition between different cell types for nutrients in the TIME [ 10 ]. Further, we suggest potential therapeutic strategies targeting metabolic reprogramming of cancer and immune cells in the TIME to overcome the resistance to anticancer immune therapy.…”