Don't Weight! Obesity and Cancer

While most people associate excess weight with diabetes and heart disease, obesity is also connected to an increased risk of several different cancers, in addition to a worse prognosis and survival rate.Researchers have discovered obesity-related processes that speed tumor growth, including chronic inflammation and metabolic alterations. However, details on this connection have remained inconclusive.A recent study by Harvard Medical School scientists has found new information (through a mouse experiment) that provides evidence for cancer immunotherapy. In a competition for energy, obesity lets cancer cells outcompete tumor-destroying immune cells.The study, published in Cell in early December, found that a diet high in fat limits the numbers and antitumor activity of a critical type of immune cell called CD8 + T cells, inside tumors. This happens as cancer cells reprogram their metabolism due to improved access to fat to consume energy-intense fat molecules, starving T cells of energy and advancing tumor growth.When similar tumors are placed in obese and nonobese settings, cancer cells alter their metabolism related to a high-fat diet, according to Marcia Haigis, co-senior author of the study and professor of cell biology in the Blavatnik Institute at HMS. This suggests that a treatment that works in one setting may not work in another. Given the epidemic of obesity in society, this mechanism needs to be better understood.The researchers discovered that blocking the fat-related metabolic reset greatly reduced tumor volume in mice fed high-fat diets. The results of the study suggest new ways to improve therapies such as using CD8+ T cells, a powerful immunotherapy used to stimulate the immune system against cancer.These types of cancer immunotherapies can make a big impact on patients’ lives, but are not beneficial to everyone, according to co-author Arlene Sharpe, the HMS George Fabvan Professor of Comparative Pathology and chair of the Dept. of Immunology at the Blavatnik Institute.Sharpe calls the interchange between T cells and tumor cells a “metabolic tug of war” that changes due to obesity. "Our study provides a roadmap to explore this interplay, which can help us to start thinking about cancer immunotherapies and combination therapies in new ways."The effects of obesity were evaluated in mouse models that had different types of cancer such as melanoma, colorectal, breast, and lung cancer, according to Haigis and Sharpe. Mice were either fed normal or high-fat diets. High-fat diets led to higher body weight and other obesity-related alterations. The researchers then evaluated various cell types and molecules inside and around tumors, collectively named the tumor microenvironment.Tumors grew more rapidly in animals on high-fat diets, but this happened only in cancer types that are immunogenic -- those that have high numbers of immune cells. These are easily recognized by the immune systems and are would typically provoke an immune response.Diet-related differences in growth of tumors depended on the action of CD8+ T cells, immune cells that can target and destroy cancer cells. Diet didn’t impact tumor growth if CD8+ T cells were taken away in mice, experimentally.Surprisingly, the presence of CD8+ T cells were reduced by high-fat diets in the tumor microenvironment, but not anywhere else in the body. Those left in the tumor weren’t as strong -- they divided more slowly and showed indications of decreased activity. When these cells were separated and created in a lab, they showed normal activity, implying that there is something in the tumor that impaired the cells’ activity.The scientists also noticed a paradox in obese animals. The tumor microenvironment was devoid of free fatty acids, a source of fuel for cells, though the rest of the body was immersed in fat, which is typical in obesity. The findings encouraged the scientists to develop a comprehensive encyclopedia of metabolic profiles of various cell types in tumors considering normal and high-fat conditions.It appears that cancer cells change in response to differences in fat availability. In high-fat diets, cancer cells were able to adjust their metabolism to increase fat uptake and use, which CD8+ T cells did not. The tumor microenvironment of some fatty acids was depleted, leaving T cells without the necessary energy.The researchers were surprised at how obesity and whole-body metabolism could change how cells in tumors use energy. Their metabolic atlas helps them understand the process better.Through various approaches like single-cell gene expression analysis, large-scale protein surveys, and high-resolution imaging, the researchers found several diet-related alterations to metabolic pathways of both immune cells and cancer in the tumor microenvironment.A protein called PHD3 that’s normally in cells was shown to help slow down excessive fat metabolism. Lower expression of PHD3 was observed in cancer cells in an obese environment compared to normal circumstances. When tumor cells were forced to overexpress PHD, it lessened a tumor’s chance to take up fat in obese mice. It also restocked free fatty acids in the tumor microenvironment.The negative effects of a high-fat diet on immune cell functions in tumors were reversed with higher PHD3 expression. In obese mice, tumors with high PHD3 grew more slowly compared to those with low PHD3. This was directly related to increased CD8+ T cell activity. Obese mice without CD8+ T cells had tumor growth that was not impacted by changes in PHD3 expression.The researchers evaluated tumor databases and discovered that low PHD3 expression was linked with immunologically “cold” tumors -- those with fewer immune cells. Tumor fat metabolism is linked with human disease. Obesity lowers anti-tumor immunity in a variety of types of cancer.Sharpe notes that "CD8+ T cells are the central focus of many promising precision cancer therapies, including vaccines and cell therapies such as CAR-T," Therapies require T cells for adequate energy to kill cancer cells, but simultaneously, energy should be limited to prevent tumor growth. More comprehensive information is now available to study this connection and find ways to inhibit T cells from functioning as they should.The authors assert that it’s too early to say if PHD3 is the best therapeutic target, but the ability to new ways to fight cancer through understanding the impact of obesity is promising. Their research in finding immune antitumor function is just beginning, with several other methods to be investigated (1).For those working with clients at high risk for cancer, below are a few ideas for obesity management:

• Don’t dance around the subject. Discuss the risks of carrying extra weight.
• Encourage sustainable changes, such as increased water consumption and consistent exercise.
• Provide plant-based recipes. Research shows a reduced cancer risk with increased intake of fruits and vegetables.
• Reduce red meat and processed meat. Both have been linked with several cancers including colorectal, breast, gastric and prostate cancer (2, 3).
• Exercise regularly. This has been found to inhibit tumor growth and aid in weight management (4).

By Lisa Andrews, MEd, RD, LDReferences:

1. Alison E. Ringel, Jefte M. Drijvers, Gregory J. Baker, Alessia Catozzi, Juan C. García-Cañaveras, Brandon M. Gassaway, Brian C. Miller, Vikram R. Juneja, Thao H. Nguyen, Shakchhi Joshi, Cong-Hui Yao, Haejin Yoon, Peter T. Sage, Martin W. LaFleur, Justin D. Trombley, Connor A. Jacobson, Zoltan Maliga, Steven P. Gygi, Peter K. Sorger, Joshua D. Rabinowitz, Arlene H. Sharpe, Marcia C. Haigis. Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity. Cell, 2020; DOI: 10.1016/j.cell.2020.11.009
2. Diallo A, Deschasaux M, Latino-Martel P, Hercberg S, Galan P, Fassier P, Allès B, Guéraud F, Pierre FH, Touvier M. Red and processed meat intake and cancer risk: Results from the prospective NutriNet-Santé cohort study. Int J Cancer. 2018 Jan 15;142(2):230-237
3. Zhao Z, Yin Z, Zhao Q. Red and processed meat consumption and gastric cancer risk: a systematic review and meta-analysis. Oncotarget. 2017 May 2;8(18):30563-30575
4. Hojman P, Gehl J, Christensen JF, Pedersen BK. Molecular Mechanisms Linking Exercise to Cancer Prevention and Treatment. Cell Metab. 2018 Jan 9;27(1):10-21.