Metabolic regulation of the cancer-immunity cycle

• Published in: Trends in immunology 2021-11, Vol.42 (11), p.975-993
• Main Authors: Somarribas Patterson, Luis F., Vardhana, Santosha A.
• Format: Article
• Language: English
• Subjects: Antigens; Apoptosis; Cancer; CAR-T cells; Cell growth; Chimeric antigen receptors; Enzymes; Fibroblasts; glycolysis; Growth factors; Humans; Hypoxia; Immune checkpoint; Immune system; Immunosurveillance; Immunotherapy; Kidney cancer; Kinases; lactate; Leukemia; Lung cancer; Lymphocytes; Lymphocytes T; Mammals; Melanoma; Metabolism; Mutagenesis; Mutation; Neoplasms; PD-1; Proteins; Senescence; tumor immunology; Tumor Microenvironment; Tumorigenesis; Tumors
• ISSN: 1471-4906; 1471-4981
• DOI: 10.1016/j.it.2021.09.002

The cancer-immunity cycle (CIC) comprises a series of events that are required for immune-mediated control of tumor growth. Interruption of one or more steps of the CIC enables tumors to evade immunosurveillance. However, attempts to restore antitumor immunity by reactivating the CIC have had limited success thus far. Recently, numerous studies have implicated metabolic reprogramming of tumor and immune cells within the tumor microenvironment (TME) as key contributors to immune evasion. In this opinion, we propose that alterations in cellular metabolism during tumorigenesis promote both initiation and disruption of the CIC. We also provide a rationale for metabolically targeting the TME, which may assist in improving tumor responsiveness to chimeric antigen receptor (CAR)-transduced T cells or immune checkpoint blockade (ICB) therapies. Elevated tumor glycolysis and lactate production are robust suppressors of antitumor immunity in multiple cancer subtypes.Loss of mitochondrial function is a hallmark of CD8+ T cell exhaustion and might be a promising metabolic target for improving patient responses to CAR-T and/or ICB therapy, pending future investigations.IL4I1-driven tryptophan catabolism and aryl hydrocarbon receptor activation may constitute a resistance mechanism to ICB and/or IDO1 inhibitors across cancer subtypes.We propose that the metabolic profile of the TME promotes both initiation and disruption of the cancer-immunity cycle. Hence, targeting cellular metabolism in the TME may improve responsiveness to T cell-based immunotherapies.