Obesity has assumed epidemic proportions in the Western world and has been linked to cancer. It is known for several years that obesity is an important risk factor for developing about 13 different types of cancer, including liver, pancreatic, uterine, thyroid and colorectal cancer [1] and that the incidence of these cancers is rising steadily [1,2] in obese populations. Despite this association, it is not completely understood how obesity causes increased cancer incidence.
Multiple mechanisms have been put forth to explain this association [3]. Obesity is associated with dysregulated metabolism such as insulin resistance, hyperglycemia and dyslipidemia. In addition, an expansion of adipose compartment during obesity leads to adipose dysfunction. Adipose tissue is an important endocrine organ that secretes many hormones and chemokines. Dysregulation of adipose compartment leads to skewed secretion of these factors, leading to inflammation and tumor growth. Obesity induces increase in chronic inflammation, a well-known cancer mediator. Also studies suggest that certain cells within the adipose tissue, such as cancer associated adipocytes and adipose-derived stem cells, promote tumor growth as they enter the tumor microenvironment (TME). TME is composed of several cell types including stromal cells, tumor cells and immune cells. Immune cells, such as T-cells, are meant to keep tumors in check. Decreased number of immune cells lead to evasion of anti-tumor response, promoting tumor growth.
Despite a few studies, there are huge gaps in our understanding of links between obesity-induced dysregulated metabolism and its tumor promoting effect. A recent interesting study in Cell reports that obesity nurtures a tumor microenvironment that reduces T-cell mediated immunity and augments tumor growth [4]. Administration of high fat diet induced differential effects in various tumors depending upon their immunogenicity. Highly immunogenic orthotopic E0771 breast tumors and MC38 colorectal adenocarcinoma cells grew faster in high fat diet (HFD) fed animals, while moderately immunogenic B16 melanoma tumors exhibited a modest increase and the growth rate of a poorly immunogenic lung carcinoma did not change with high fat diet. Further, they could demonstrate that HFD induced changes in tumor growth was due to reduced protective effect of anti-tumor CD8+T cells [4].
To understand how HFD feeding alters the immune landscape of MC38 colorectal adenocarcinoma, they employed flow cytometry to profile tumor-infiltrating immune cell populations in tumors 10–14 days after implantation, when tumors were similar in volume [4]. Interestingly, they observed that HFD reduces the number and functionality of intratumoral CD8+T cells while the ratio of other T-cell types such as CD4+T cells were unaltered. Further, they asked if obesity affects T-cell infiltration within the TME and if the positions of T-cells within tumors changed in response to changes in metabolic niches within the TME. To address this, they created an atlas of immune, tumor, and stromal cell populations of the TME to map their locations within the TME, and identify key features of their metabolic state. Visualization of these cell populations showed that while CD8+T cells are found within HFD tumors, HFD feeding changes metabolic niche interactions within tumors, thereby impacting local T cell infiltration patterns. These data point to a role of diet in impacting the distribution of protective immune cells within the tumors.
Both tumor cells and T-cells thrive on nutrients. Activated T-cells are highly proliferative and need specific pathways of metabolism to maintain their protective function. In this study [4], authors show that obesity/high fat diet induces metabolic changes that causes a tug of war for nutrients between cancer cells and T-cells wherein the cancer cells win! The limited nutrients feed the cancer cells but deprives the protective T-cells, thereby promoting the growth of cancer cells but hindering growth of protective T-cells, leading to evasion of anti-tumor immune responses. They could see this phenomenon by employing single-cell metabolic profiling which revealed that immune cells in the TME undergo unique metabolic adaptations in response to HFD. Interestingly, tumor cells and CD8+T cells appear to rewire their metabolism differently in response to HFD. While tumor cells adapt to this diet and increase fatty acid utilization, CD8+T cells do not [4].
Importantly, they found a gene called PHD3 to be expressed at lower levels in obese patients with BMI more than 30 kg/m2 than in non-obese patients [4]. PHD3 expression was also found to be significantly lower in colon adenocarcinoma patients as compared to normal individuals. A correlation was found between PHD3 downregulation and reduced immunity mediated by CD8+ T-cells in multiple cancer types. Interestingly, PHD3 overexpression in tumor cells led to restoration of anti-tumor immunity with significantly increased CD8+T cell infiltration in HFD animals. These findings highlight the crucial role of metabolism in immune regulation and driving tumor outcomes and tell us why immune therapies do not work in all instances. It also highlights that diet is an important contributing factor impacting the outcome of immunotherapies in various tumor types.
REFERENCES
1 Lauby-Secretan, B., Scoccianti, C., Loomis, D., Grosse, Y., Bianchini, F., Straif, K. & International Agency for Research on Cancer Handbook Working, G. Body Fatness and Cancer–Viewpoint of the IARC Working Group. N Engl J Med, 2016, 375, 794-798, doi:10.1056/NEJMsr1606602.
2 Sung, H., Siegel, R. L., Torre, L. A., Pearson-Stuttard, J., Islami, F., Fedewa, S. A., Goding Sauer, A., Shuval, K., Gapstur, S. M., Jacobs, E. J., Giovannucci, E. L. & Jemal, A. Global patterns in excess body weight and the associated cancer burden. CA Cancer J Clin, 2019, 69, 88-112, doi:10.3322/caac.21499.
3 Deng, T., Lyon, C. J., Bergin, S., Caligiuri, M. A. & Hsueh, W. A. Obesity, Inflammation, and Cancer. Annu Rev Pathol, 2016, 11, 421-449, doi:10.1146/annurev-pathol-012615-044359.
4 Ringel, A. E., Drijvers, J. M., Baker, G. J., Catozzi, A., Garcia-Canaveras, J. C., Gassaway, B. M., Miller, B. C., Juneja, V. R., Nguyen, T. H., Joshi, S., Yao, C. H., Yoon, H., Sage, P. T., LaFleur, M. W., Trombley, J. D., Jacobson, C. A., Maliga, Z., Gygi, S. P., Sorger, P. K., Rabinowitz, J. D., Sharpe, A. H. & Haigis, M. C. Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity. Cell, 2020, 183, 1848-1866 e1826, doi:10.1016/j.cell.2020.11.009.
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