July's Paper of the Month looks at how obesity shapes metabolism in the tumour microenvironment to suppress anti-tumour immunity.
Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity
AE Ringel, JM Drijvers, GJ Baker, A Catozzi, JC García-Cañaveras, Gassaway BM, Miller BC, Juneja VR, Nguyen TH, Joshi S, Yao CH, Yoon H, Sage PT, LaFleur MW, Trombley JD, Jacobson CA, Maliga Z, Gygi SP, Sorger PK, Rabinowitz JD, Sharpe AH, Haigis MC.
Cell. 2020 Dec 23;183(7):1848-1866.e26. doi: 10.1016/j.cell.2020.11.009. Epub 2020 Dec 9. PMID: 33301708; PMCID: PMC8064125.
What is known about the subject?
Obesity may increase the risk of cancer by the imbalance of various mechanisms including insulin and insulin-like growth factor1 (IGF-I) signalling, systemic inflammation, immune dysregulation, tumour angiogenesis, adipokines secretion, and intestinal microbiota that usually act interdependently [1,2]. But how differences in systemic metabolism change the tumour microenvironment (TME) and impact anti-tumour immunity is not understood [3]. An increased understanding of the mechanisms underlying obesity-gastro-intestinal cancer link can provide multiple opportunities for cancer prevention.
What the study adds?
The study demonstrated that high-fat diet (HFD)-induced obesity impairs CD8+ T cell function in the murine TME, accelerating tumor growth. The authors generated a single-cell atlas of cellular metabolism in the TME, detailing how it changes with diet-induced obesity. The study showed that CD8+ T cells display metabolic adaptations to obesity. Tumor cells increase fat uptake with HFD, whereas tumor-infiltrating CD8+ T cells do not. These differential adaptations lead to altered fatty acid partitioning in HFD tumor, impairing CD8+ T cells infiltration and function. Blocking metabolic reprogramming by tumor cells in obese mice improves anti-tumor immunity. Analysis of human cancers reveals similar transcriptional changes in CD8+ T cells markers, suggesting interventions that exploit metabolism to improve cancer immunotherapy [3].
Implications for colorectal practice
This study has important clinical and research implications.
Patients’ counselling by colorectal surgeons about diet and obesity is part of colorectal cancer prevention. The research implication is shown in the strength of research methodology applied in this study. The questions posed and addressed by the researchers to test their results are a good inspirations for academic colorectal surgeons when conducting clinical research.
References
- Moodi M, Tavakoli T, Tahergorabi Z. Crossroad between Obesity and Gastrointestinal Cancers: A Review of Molecular Mechanisms and Interventions. Int J Prev Med. 2021 Feb 24;12:18. doi: 10.4103/ijpvm.IJPVM_266_20. PMID: 34084315; PMCID: PMC8106288.
- Sawicki T, Ruszkowska M, Danielewicz A, Niedźwiedzka E, Arłukowicz T, Przybyłowicz KE. A Review of Colorectal Cancer in Terms of Epidemiology, Risk Factors, Development, Symptoms and Diagnosis. Cancers (Basel). 2021 Apr 22;13(9):2025. doi: 10.3390/cancers13092025. PMID: 33922197; PMCID: PMC8122718.
- Ringel AE, Drijvers JM, Baker GJ, Catozzi A, García-Cañaveras JC, Gassaway BM, Miller BC, Juneja VR, Nguyen TH, Joshi S, Yao CH, Yoon H, Sage PT, LaFleur MW, Trombley JD, Jacobson CA, Maliga Z, Gygi SP, Sorger PK, Rabinowitz JD, Sharpe AH, Haigis MC. Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity. Cell. 2020 Dec 23;183(7):1848-1866.e26. doi: 10.1016/j.cell.2020.11.009. Epub 2020 Dec 9. PMID: 33301708; PMCID: PMC8064125.