Diet, nutrient supply, and tumor immune responses

Metabolites are key regulators of immune and tumor cells in the tumor microenvironment (TME), and the TME metabolome is heavily influenced by diet.Obesity and high-fat diets favor tumor growth through direct effects on tumor cells and via impairing antitumor immunity, partly through altering or restricting metabolism.Dietary modifications may be beneficial in conjunction with cancer therapy and could be tailored to specific tumor types. Nutrients are essential for cell function. Immune cells operating in the complex tumor microenvironment (TME), which has a unique nutrient composition, face challenges of adapting their metabolism to support effector functions. We discuss the impact of nutrient availability on immune function in the tumor, competition between immune cells and tumor cells for nutrients, and how this is altered by diet. Understanding which diets can promote antitumor immune responses could open a new era of treatment, where dietary modifications can be used as an adjunct to boost the success of existing cancer therapies. Nutrients are essential for cell function. Immune cells operating in the complex tumor microenvironment (TME), which has a unique nutrient composition, face challenges of adapting their metabolism to support effector functions. We discuss the impact of nutrient availability on immune function in the tumor, competition between immune cells and tumor cells for nutrients, and how this is altered by diet. Understanding which diets can promote antitumor immune responses could open a new era of treatment, where dietary modifications can be used as an adjunct to boost the success of existing cancer therapies. Metabolic pathways play an essential role in regulating immune fate and function. Systemic metabolism, particularly in metabolic organs including liver, adipose, and muscle, as well as the gut, provides circulating metabolites. These pathways are highly influenced by dietary nutrients. Diet directly provides nutrients, but many nutrients are transformed into metabolic intermediates by the microbiota and metabolic processes in tissues (Figure 1). At the cellular level, immune cells sense nutrient availability and access these nutrients via extracellular uptake. In addition, immune cells have intrinsic processes to recycle nutrients or synthesize them de novo. The TME has distinct nutrient availability compared with circulation or tissues under homeostatic conditions. The rapid expansion of tumor cells is metabolically demanding, and tumors consume high levels of fuel to support this. At the same time, immune cells within the TME have metabolic requirements to function, which can overlap with those of tumor cells. This creates a complex and competitive environment, where the tumor often wins. Understanding the nutrient requirements of both tumor and immune cells in the TME may enable new therapeutic approaches to treat or prevent cancer by altering metabolism, through dietary supply of nutrients. In this review, we will focus on the impact of extracellular nutrient supply on immune function in the tumor, how this is influenced by diet, and the potential for targeting nutrient supply to enhance cancer therapies. The TME has a distinct nutrient pattern. Indeed, tumors are detected by positron emission tomography (PET) scans because of their enriched glucose or glutamine utilization compared with healthy tissue. The field of tumor metabolism and immunometabolism now has an intense focus on which metabolites are enriched in the TME, and whether they fuel tumor growth or fuel the immune system. Understanding this will hopefully allow modulation toward a metabolic environment that would impede tumor growth by depriving nutrients that fuel tumor proliferation and metastasis while at the same time, providing nutrients that maximally fuel antitumor immunity. A comprehensive metabolic analysis of tumor interstitial fluid (TIF) from murine pancreatic ductal adenocarcinoma, compared with serum found lower levels of glucose, pyruvate, and arginine in the tumor [1.Sullivan M.R. et al.Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability.eLife. 2019; 8e44235Crossref Scopus (256) Google Scholar], suggestive of increased uptake by cells in the TME. Given that cancer can be detected by PET scan for high glucose uptake, it is generally appreciated that many tumors have high glucose uptake, and that the immune system, therefore, functions in a low glucose state in the TME. In highly glycolytic tumors, some tumor cell types engage in aerobic glycolysis, which causes increased lactate levels in the TME. Lactate suppresses effector T cell responses [2.Quinn W.J. et al.Lactate limits T Cell proliferation via the NAD(H) redox state.Cell Rep. 2020; 33108500Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar] and supports regulatory T cell (Treg) function to promote growth in B16 and MC38 models [3.Watson M.L.J. et al.Metabolic support of tumour-infiltrating regulatory T cells by lactic acid.Nature. 2021; 591: 645-651Crossref PubMed Scopus (350) Google Scholar]. Levels of amino acids (glutamate, aspartate, and glycine) are increased in TIF, and there is a higher abundance of free fatty acids, acylcarnitines, ceramides, and esterified cholesterol [4.Xu S. et al.Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors.Immunity. 2021; 54: 1561-1577.e7Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar]. It is therefore important to understand the effect of nutrients that are enriched in the tumor on immune function, and the effect of an environment depleted of certain nutrients, like glucose. In recent years, our understanding of immune cell metabolism has rapidly expanded [5.Makowski L. et al.Immunometabolism: from basic mechanisms to translation.Immunol. Rev. 2020; 295: 5-14Crossref PubMed Scopus (141) Google Scholar,6.Leone R.D. Powell J.D. Metabolism of immune cells in cancer.Nat. Rev. Cancer. 2020; 20: 516-531Crossref PubMed Scopus (303) Google Scholar]. This adds complexity, as different immune cells require different nutrients to function. For example, Th17 cells rely on glutamine, Tregs rely on fatty acid oxidation (FAO), and Th1 cells predominantly rely on glycolysis [7.Gerriets V.A. et al.Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation.J. Clin. Investig. 2015; 125: 194-207Crossref PubMed Scopus (487) Google Scholar, 8.Michalek R.D. et al.Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets.J. Immunol. 2011; 186: 3299-3303Crossref PubMed Scopus (1426) Google Scholar, 9.Johnson M.O. et al.Distinct regulation of Th17 and Th1 cell differentiation by glutaminase-dependent metabolism.Cell. 2018; 175: 1780-1795.e19Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar]. Further, the immune composition in the tumor varies depending on the cancer type, stage of disease, and anatomical location, all of which influence local nutrient composition. Therefore, a better understanding of the holistic effect of dietary nutrients on the whole TME is required to promote a better antitumor immune response. Immune cells present in the tumor must compete with other cells for nutrients to fulfill their metabolic and growth needs. Tumor cells avidly take up fuels to support uncontrolled proliferation. Although the specific nutrient requirements of tumor cells will vary depending on the origin, genetic mutations, and stage of disease, in many instances nutrient requirements overlap with immune cells. A central dogma in the field has been that tumor cells are highly reliant on glucose [10.Potter M. et al.The Warburg effect: 80 years on.Biochem. Soc. Trans. 2016; 44: 1499-1505Crossref PubMed Scopus (311) Google Scholar]. Effector CD4 and CD8 T cells, which both play crucial roles in antitumor immunity, require glucose and amino acids for their cytotoxic functions [11.Cham C.M. et al.Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8+ T cells.Eur. J. Immunol. 2008; 38: 2438-2450Crossref PubMed Scopus (279) Google Scholar, 12.Masson J.J.R. Palmer C.S. Glucose metabolism in CD4 and CD8 T cells.in: Molecular Nutrition: Carbohydrates. Elsevier, 2019: 129-147Crossref Scopus (2) Google Scholar, 13.Ma E.H. et al.Metabolic profiling using stable isotope tracing reveals distinct patterns of glucose utilization by physiologically activated CD8+ T cells.Immunity. 2019; 51: 856-870.e5Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 14.Jones N. et al.Metabolic adaptation of human CD4+ and CD8+ T-cells to T-cell receptor-mediated stimulation.Front. Immunol. 2017; 8: 1516Crossref PubMed Scopus (54) Google Scholar]. Downstream of T cell receptor (TCR) signaling, CD8 T cells upregulate GLUT1, increase glucose intake, and activate downstream glycolysis and mTORC1 [15.Siska P.J. et al.Suppression of Glut1 and Glucose metabolism by decreased Akt/mTORC1 signaling drives T cell impairment in B cell leukemia.J. Immunol. 2016; 197: 2532Crossref PubMed Scopus (100) Google Scholar]. Thus, glucose restriction in the tumor impairs T cell cytotoxicity [16.Ho P.C. et al.Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses.Cell. 2015; 162: 1217-1228Abstract Full Text Full Text PDF PubMed Scopus (919) Google Scholar]. Glucose levels detected in TIF were lower than circulation or spleen, likely due to preferential glucose uptake by tumor cells. Th1 cell glucose uptake was reduced in the presence of tumor cells in vitro and low glucose in the TME can impair CD8 T cell function [16.Ho P.C. et al.Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses.Cell. 2015; 162: 1217-1228Abstract Full Text Full Text PDF PubMed Scopus (919) Google Scholar, 17.Chang C.H. et al.Metabolic competition in the tumor microenvironment is a driver of cancer progression.Cell. 2015; 162: 1229-1241Abstract Full Text Full Text PDF PubMed Scopus (1871) Google Scholar, 18.Siska P.J. et al.Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma.JCI Insight. 2017; 2e93411Crossref PubMed Scopus (213) Google Scholar] (Figure 2). In addition, the TME is often hypoxic, which induces GLUT1 expression for increased glucose uptake. However, if glucose is not available because it is being sequestered by tumor cells, CD8 T cells can switch to FAO to fuel their functions [19.Zhang Y. et al.Enhancing CD8+ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy.Cancer Cell. 2017; 32: 377-391.e9Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar]. In vivo tracing showed increased use of fatty acids instead of glucose for the tricarboxylic acid cycle (TCA) cycle. By enhancing FA catabolism, CD8 T cell cytotoxicity was boosted in a hypoxic low glucose context. However, while this adaptation maintained some cytotoxic functions, it was not optimal for CD8 T cells, as they had induced hallmarks of exhaustion. More recent work challenges the dogma that tumor cells cause glucose restriction for other cells in the TME [20.Reinfeld B.I. et al.Cell-programmed nutrient partitioning in the tumour microenvironment.Nature. 2021; 593: 282-288Crossref PubMed Scopus (335) Google Scholar]. In multiple tumor models (MC38, CT26, Renca, AOM/DSS, PyMT GEMM), they showed glucose utilization was highest in myeloid cells, followed by tumor cells and then T cells within the tumor. By contrast, tumor cells were more dependent on glutamine. A major determinant of glucose usage by tumor cells was glutamine, as when glutamine metabolism was inhibited, tumor cells increased their glucose uptake (Figure 2). Glutamine is also highly utilized by activated CD8 T cells [21.Carr E.L. et al.Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation.J. Immunol. 2010; 185: 1037-1044Crossref PubMed Scopus (521) Google Scholar]. This creates potential competition between T cells and tumor cells, in scenarios where tumors also rely on glutamine. This concept is supported by a study using the E0771 breast cancer model, where glutamine metabolism was targeted specifically in tumor cells, leading to decreased growth and enhanced antitumor CD8 T cell responses [22.Edwards D.N. et al.Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer.J. Clin. Invest. 2021; 131e140100Crossref Scopus (108) Google Scholar]. In addition to glucose and glutamine, lipids are a major nutrient source in TME, and typically support tumor growth [4.Xu S. et al.Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors.Immunity. 2021; 54: 1561-1577.e7Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar]. However, several studies have described the suppressive effects of lipids on CD8 T cells. High cholesterol in the TME suppressed CD8 T cell effector functions and enhanced exhaustion due to endoplasmic reticulum stress [23.Ma X. et al.Cholesterol induces CD8+ T cell exhaustion in the tumor microenvironment.Cell Metab. 2019; 30: 143-156.e5Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar]. Similarly, accumulation of long-chain fatty acids within CD8 T cells impaired mitochondrial function. Additionally, uptake of oxidized low-density lipoproteins via scavenger receptor CD36 led to lipid peroxidation and ferroptosis, which dampened CD8 T cell cytotoxic function and enhanced exhaustion [4.Xu S. et al.Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors.Immunity. 2021; 54: 1561-1577.e7Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar,24.Ma X. et al.CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability.Cell Metab. 2021; 33: 1001-1012.e5Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar]. Antigen presentation is also impacted by high lipids in the tumor. Dendritic cells can take up lipids from the TME via macrophage scavenger receptor, which impairs their antigen processing and subsequent activation of T cells [25.Herber D.L. et al.Lipid accumulation and dendritic cell dysfunction in cancer.Nat. Med. 2010; 16: 880-886Crossref PubMed Scopus (473) Google Scholar]. By contrast, high expression of CD36 on intra-tumoral Tregs enhances their suppressive functions to promote tumor growth [26.Wang H. et al.CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors.Nat. Immunol. 2020; 21: 298-308Crossref PubMed Scopus (258) Google Scholar]. Another important study showed that Tregs in the tumor upregulate SREBP for lipid synthesis which is important for their survival and suppressive functions in the tumor [27.Lim S.A. et al.Lipid signalling enforces functional specialization of Treg cells in tumours.Nature. 2021; 591: 306-311Crossref PubMed Scopus (141) Google Scholar]. Similar to Tregs, lipids are also important for tumor-enhancing features of interleukin (IL)-17 producing γδ T cells. Treatment with lipase inhibitor orlistat, which decreases the release of free fatty acids, reduced IL-17+ γδ T cells in the tumor and was associated with decreased tumor growth [28.Lopes N. et al.Distinct metabolic programs established in the thymus control effector functions of γδ T cell subsets in tumor microenvironments.Nat. Immunol. 2021; 22: 179-192Crossref PubMed Scopus (66) Google Scholar]. These studies suggest that despite tumor cell reliance on lipids as a fuel source, their abundance is sufficient for uptake by immune cells. It is likely this nutrient demand/interplay changes depending on the type of tumor. Comparison of metabolism in two melanoma cell lines, immunologically 'cold' YUMM1.7 to 'hot' YUMMER1.7 cells, revealed an association between tumor cell glutamine metabolism and immune infiltration [29.Zhang X. et al.Isotope tracing reveals distinct substrate preference in murine melanoma subtypes with differing anti-tumor immunity.Cancer Metab. 2022; 10: 21Crossref PubMed Google Scholar]. In human melanoma samples, expression of glutamine transporters also correlated with lymphocyte infiltration and function. Further work is required to show a direct link between the decreased immune infiltrate in 'cold' tumors and lower glutamine usage by tumor cells. It could be speculated that when tumor cells are more reliant on glutamine, this increases glucose availability for immune function. In mouse models, tumor location can influence the metabolic makeup of TIF [1.Sullivan M.R. et al.Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability.eLife. 2019; 8e44235Crossref Scopus (256) Google Scholar]. For example, pancreatic ductal adenocarcinoma cells injected subcutaneously showed differences in metabolite abundance compared with autochthonous tumors. This was not due to tumor size, but location, as metabolite levels were unchanged between small or large tumors. Whether this difference is due to altered nutrient supply, growth dynamics of tumor cells, or a difference in immune cell infiltration, remains to be determined. In line with these findings, only a few common metabolites have been found across different types of human tumor [30.Reznik E. et al.A landscape of metabolic variation across tumor types.Cell Syst. 2018; 6: 301-313.e3Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar]. An integration of metabolic analysis from 900 tissue samples isolated from seven different cancer types and found that lactate, carnitines, and kynurenine were commonly enriched in tumors compared with normal tissue. However, most metabolite levels varied across different tumors. Research on how altered nutrient supply in different tumor types or location impacts the immune response is limited. While significant progress has been made in understanding nutrient availability in the tumor through analysis of TIF, this does not provide information on the localization of nutrients within the complex tumor architecture. Nor does it consider competition between cells within the tumor, particularly when supply of some nutrients is limited, and different cell types have different nutrient preferences. New approaches, such as spatial metabolomics [31.Andersen M.K. et al.Spatial differentiation of metabolism in prostate cancer tissue by MALDI-TOF MSI.Cancer Metab. 2021; 9: 1-13Crossref PubMed Google Scholar,32.He M.J. et al.Comparing DESI-MSI and MALDI-MSI mediated spatial metabolomics and their applications in cancer studies.Front. Oncol. 2022; 12891018Google Scholar], have begun to shed light on some of these questions. In a breast cancer model, image cytometry and mathematical modeling found macrophage differentiation in distinct regions of the tumor due to localized lactate levels, related to ischemia and relative position to the vasculature [33.Carmona-Fontaine C. et al.Metabolic origins of spatial organization in the tumor microenvironment.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 2934-2939Crossref PubMed Scopus (209) Google Scholar]. Another approach uses photoconversion of areas to dissect micro-environments (PADME-seq), which combines photo-labeling, cell sorting, and single-cell RNA sequencing of immune cells from specific tumor regions [34.Baldominos P. et al.Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche.Cell. 2022; 185: 1694-1708.e19Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar]. Authors identified a niche of quiescent cancer cells (4T07 mammary carcinoma model), which form subterritories with reduced immune infiltration and increased exhaustion, driven by HIF1a expression in tumor cells. This work highlights the heterogeneity within the TME and how specific regions have distinct immune populations. Tumor vascularization has a major influence on regional nutrient supply in the TME. Rapid tissue expansion requires angiogenesis to provide nutrients and oxygen supply to the tumor. Proximity to blood vessels can influence the metabolism of tumor cells [35.Kumar S. et al.Intra-tumoral metabolic zonation and resultant phenotypic diversification are dictated by blood vessel proximity.Cell Metab. 2019; 30: 201-211.e6Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar], and this is also likely true for immune cells. Nutrient supply via blood may also differ depending on the location in the body. For example, ascites, an accumulation of peritoneal fluid which can occur with cancers such as ovarian cancer, was initially proposed to be a nutrient-deprived site. However, more recent studies have shown that it is not deficient in nutrients such as glucose, possibly due to proximity to metabolic organs [36.Gong Y. et al.Metabolic factors contribute to T-cell inhibition in the ovarian cancer ascites.Int. J. Cancer. 2020; 147: 1768-1777Crossref PubMed Scopus (15) Google Scholar]. Further studies are required to uncover how regional localization of nutrients impact immunity within the tumor. Diet has a major influence on nutrient supply and metabolite species in the whole body and in tumors. The type of diet also affects tumor growth. Approximately 20% of cancer mortalities can be attributed to diet [37.Blot W.J. Tarone R.E. Doll and Peto's quantitative estimates of cancer risks: Holding generally true for 35 years.J. Natl. Cancer Inst. 2015; 107: 44Crossref Scopus (39) Google Scholar]. Alterations to diet can have a profound effect on immune responses, both systemically and within the tumor. While much research has been done on the impact of diet on health, there is renewed interest in understanding the impact of diet on tumor growth and on the immune response to cancer at the molecular level (summarized in Table 1). For patients, information surrounding diet and cancer is often confusing and conflicting. Uncovering how specific diets alter immune function in the tumor could create new therapeutic opportunities for cancer patients to use diet to fuel the antitumor immune response.Table 1The impact of major nutrient changes with diet on immune cells and tumor growthaAbbreviations: AAs, amino acids; Carbs, carbohydrates; chol, cholesterol; DC, dendritic cell; FAs, fatty acids; gzmb, granzyme B; IFNγ, interferon gamma; MMP, matrix metalloproteinase; NK, natural killer; TGFβ, transforming growth factor beta; TNFα, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor; +, increased; –, decreased; =, unchanged.DietNutrient compositionNutrient changes in vivoImpact on immune cellsImpact on tumor growthRefsHigh fat+ Fat+/= Chol (variable)+ Glucose, insulin, FAs, cholDecreased: CD8 T cells, NK cells (production of TNFα, IFNγ, Gzmb)Increased: macrophages/neutrophils/DCs (IL-10, MMMP, VEGF)Increased or unchanged (depending on fat source)[28.Lopes N. et al.Distinct metabolic programs established in the thymus control effector functions of γδ T cell subsets in tumor microenvironments.Nat. 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Cancer Res. 2018; 24: 6383-6395Crossref PubMed Scopus (54) Google Scholar]High fiber+ Fiber+ Short-chain FAsNot describedDecreased[81.Li Y. et al.Prebiotic-induced anti-tumor immunity attenuates tumor growth.Cell Rep. 2020; 30: 1753-1766.e6Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar,83.Donohoe D.R. et al.A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner.Cancer Discov. 2014; 4: 1387-1397Crossref PubMed Scopus (315) Google Scholar]a Abbreviations: AAs, amino acids; Carbs, carbohydrates; chol, cholesterol; DC, dendritic cell; FAs, fatty acids; gzmb, granzyme B; IFNγ, interferon gamma; MMP, matrix metalloproteinase; NK, natural killer; TGFβ, transforming growth factor beta; TNFα, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor; +, increased; –, decreased; =, unchanged. Open table in a new tab High-fat diet (HFD), which is typically 45–60% of calories fro