Obesity prevalence has increased significantly in the past few decades, representing one of the major public health problems of this century. Indeed, obesity is associated with several human diseases, such as vascular diseases and diabetes. Several studies have shown that obesity is a risk factor for cancer. For instance, obesity induces changes of systemic metabolism and changes (epigenetic and transcriptional) in cells of the intestinal epithelium that favor tumor initiation in colorectal cancer.
Tumor microenvironment is the region surrounding the tumor mass, which contains tumor cells, cells of the immune system and stromal cells, interacting and affecting each other’s. Highly proliferating tumor cells are characterized by increased nutrient consumption; activated immune T cells (T cells are a subtype of white blood cells) infiltrating the tumor mass are highly proliferative and require specific metabolic pathways.
Tumor microenvironment is known to play a key role in tumor progression, however it is not known how mechanistically systemic metabolic changes occurring in obese cancer patients contribute to increase cancer risk.
Main finding. In a recent paper published in Cell, authors have shown how changes in systemic metabolism –induced by high fat diet in mouse models– induce local metabolic changes at the tumor microenvironment, and how that, in turn, inhibits T cell function and promotes tumor growth.
In particular, they show that in mouse models fed with high fat diet (to make the mice gain weight and simulate obesity) tumor cells are reprogrammed, upregulating the specific cell pathways related to free fatty acids. Tumor cell reprogramming causes depletion of free fatty acids from the tumor microenvironment. Blocking tumor cell reprogramming results into increased availability of free fatty acids in the tumor microenvironment, which in turn enables better control of tumor progression by the immune system.
Experimental details. Authors employed mice fed with high fat diet as a model system. These mice gained weight and showed metabolic alteration associated with human obesity. Obese mice were then injected with different tumor cell types: immunogenic (“immunogenic”: able to induce an immune response) tumor cells grew faster in obese mice, whereas less immunogenic tumor cells’ growth was not affected, suggesting that cells of the immune system were somehow involved in tumor growth.
How specifically cells of the immune system were involved?
Tumor cell growth. Colorectal cancer cells (MC38) were injected in transgenic mice lacking T cells. Mice fed with high fat diet gained weight and displayed the typical metabolic changes observed also in control animals (which have T cells); however, in mice lacking T cells the increased weight did not affect tumor cell growth, which resulted to be the same in mice fed standard diet.
Number and functionality of tumor infiltrating immune cells. Tumors isolated from high fat diet fed mice showed lower numbers of infiltrating T cells (CD8+ subtype), higher numbers of cd11b myeloid cells and tumor associated macrophages (F4/80+ GR1 CD11b+); the latter ones are cell types known to promote tumor growth. CD4 subtype T cells, NK and dendritic cell (which are known to stimulate T cells) numbers in tumors of mice fed with high fat diet were not affected.
Tumor infiltrating CD8 T cells of mice fed high fat diet were less proliferative and less active.
Interestingly, when these cells were cultured in vitro, they appeared similar to those isolated from mice fed a standard diet, demonstrating that the alteration observed in vivo was specifically related to the microenvironment of a high fat diet and was not due to an intrinsic defect in T cell activation. However, not all tumor types tested were affected the same way.
Tumor and T cell reprogramming in high fat diet. In detail, how does a high fat diet differentially affect tumor cells and T cells, meaning, what are the metabolic changes induced in tumor and T cells?
Experiments highlighted changes in fat metabolism –mirroring cell adaptation to high fat diet-induced conditions– that were specific to tumor and T cells: tumor cells from high fat diet-fed mice took up more fatty acids than those of mice fed with standard diet.
Both tumor and T cells reprogram their metabolism in high fat diet conditions, but in different ways: while tumor cells increase fatty acid utilization, T cells do not. This may be due to the fact that the increased fatty acid uptake by tumor cells decreases the amount available to T cells.
So basically high fat diet reprograms the tumor microenvironment, inducing an enhanced fat uptake by tumor cells, which may affect free fatty acid availability and in turn T cell functioning.
Interfering with high fat diet-induced changes in tumor cell restores anti-tumor T cell activity. Overexpression of PHD3 (a main regulator of the metabolic changes induced by high fat diet in colorectal cancer cells) in tumor cells prevents high fat diet-induced metabolic reprogramming and restores the activity of T cells. Active T cells are thus able to control and inhibit tumor growth occurring in high fat diet-fed mice. PHD3 overexpression does not affect in vitro tumor cell growth, demonstrating that the effect is not intrinsic to tumor cells but is determined by the microenvironment.
Interestingly, while in high fat diet-fed mice, circulating free fatty acid levels were higher, local amounts in the tumor microenvironment were lower, likely due to tumor cell reprogramming and increased uptake. PHD3 overexpression increased free fatty acid levels in the tumor microenvironment –possibly because of the consequent reduced uptake by tumor cells– ultimately restoring T cell functioning.
Obesity-induced tumor cell metabolic changes in patients. Does obesity alter tumor metabolism in patients as it does in mouse models? Analyses of gene expression data of colon carcinoma and the corresponding body mass index data showed a significantly lower PHD3 expression in tumors of obese patients, a reduced presence of tumor infiltrating CD8 T cells and reduced inflammation. Therefore, also in humans, PHD3 downregulation in cancer correlates with a reduced functionality of T cells as observed in mouse models.
Conclusions. Authors showed that changes of systemic metabolism induced by high fat diet in turn affect metabolism of cells in the tumor microenvironment. In particular, tumor cells reprogram the pathways involved in the uptake of free fatty acids from the tumor microenvironment. The reduced availability of free fatty acids causes T cell dysfunction. Dysfunctional T cells lose the ability to prevent tumor growth. Importantly, the results demonstrate that the effect of high fat diet, both on tumor cells and immune cells of the tumor microenvironment, can be reversed by PHD3 overexpression in tumor cells.
Several studies have previously found a link between diet and anti tumor immunity. For instance, low-protein diet promotes an anti-tumor immune response.
However, this work shows the
importance to consider the effect of changes in metabolism on both tumor and immune cells of the tumor microenvironment and importantly how these affect each other’s, as well as considering the
possible implication for metabolism-targeted cancer therapies.
Reference. Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity. Alison E. Ringel,Jefte M. Drijvers et al., Cell 2020.