Editors' ChoiceCancer Immunotherapy

Metabolic competition between tumors and T cells

Sci. Signal.  06 Oct 2015:
Vol. 8, Issue 397, pp. ec281
DOI: 10.1126/scisignal.aad5685

Cancer cells can evade the immune system by triggering sustained T cell dysfunction, a condition called exhaustion, or by activating immune checkpoints that inhibit T cell function, such as programmed cell death protein 1 (PD1), a receptor that binds to its ligand PD-L1. A trio of papers has revealed that aerobic glycolysis in tumors results in a glucose-poor microenvironment that causes exhaustion in T cells, which depend on aerobic glycolysis upon activation. Furthermore, PD-L1 and PD-1 not only suppress T cell function, but also enhance aerobic glycolysis in cancer cells. In mice with tumors formed from melanoma cells, Ho et al. noted that the tumor interstitial fluid had low glucose concentrations and that intratumoral CD4+ T cells took up less glucose than did those in the spleen. Compared with CD4+ T cells from the spleen or draining lymph nodes, a smaller proportion of intratumoral T cells produced CD40 ligand (CD40L), which is important for T cell activation, and interferon-γ (IFN-γ), a proinflammatory and anticancer cytokine. Tumor-infiltrating lymphocytes (TILs) in mice engrafted with melanoma cells overexpressing the glycolytic enzyme hexokinase 2 (HK2) produced less CD40L and IFN-γ than those in mice engrafted with control melanoma cells. Moreover, CD4+ T cells decreased the growth of control melanoma cells, but not that of HK2-overexpressing cells, that had been engrafted into Rag1 knockout mice (which do not produce mature T or B cells). T cell receptor (TCR) stimulation triggers Ca2+ signaling that promotes the relocalization of the transcription factor NFAT from the cytosol to the nucleus, where it transcriptionally activates genes required for T cell activation. TCR-stimulation of T helper 1 (TH1) cells in low glucose conditions resulted in reduced intracellular Ca2+ concentrations and nuclear translocation of NFAT. Inhibition of SERCA, an endoplasmic reticulum (ER)–localized Ca2+ ATPase, restored the nuclear translocation of NFAT in glucose-deprived T cells. The glycolytic metabolite phosphoenolpyruvate (PEP) inhibited Ca2+ uptake in ER vesicles from Jurkat cells through a mechanism that appeared to depend on the oxidation of cysteine residues in SERCA. Phosphoenolpyruvate carboxykinase 1 (PCK1) produces PEP, and overexpression of PCK1 in CD4+ T cells prevented the decrease in Ca2+ flux and nuclear translocation of NFAT that was caused by glucose deprivation. In mice with engrafted melanomas and that were injected with CD4+ T cells engineered to recognize a melanoma antigen, PCK1 overexpression in the T cells increased CD40L and IFN-γ production and effector function and suppressed tumor growth. In the second paper, Chang et al. used a model in which tumors with a major rejection antigen (R tumors) regress in a manner that requires IFN-γ produced by TILs. Tumors without this antigen (P tumors) do not regress. T cells produced less IFN-γ when cultured with R tumor cells and the least amount of IFN-γ when cultured with P tumor cells compared with T cells cultured alone, an effect that was rescued by the addition of glucose. The rate of aerobic glycolysis was greater in P tumor cells than in R tumor cells, whereas TILs from P tumors had the lowest aerobic glycolytic rate. The kinase-containing mTORC1 protein complex regulates anabolic processes that support cell growth and proliferation in response to nutrient availability, and the phosphorylation of two mTORC1 targets was decreased in TILs from P tumors than in those from R tumors, an effect consistent with the increased metabolism of P tumors having a more restrictive effect on glucose availability. P tumors from mice that were treated with checkpoint blockade therapy, including blocking antibodies against PD-1 or PD-L1, had higher extracellular glucose concentrations, and TILs from these mice had increased glycolytic rates, phosphorylation of mTORC1 targets, and IFN-γ production. PD-L1 blockade or RNA interference directed against PD-L1 in cultured P tumor cells resulted in decreases in the glycolytic rate, glucose uptake, and phosphorylation of mTORC1 targets. In Rag(–/–) mice transplanted with tumors expressing PD-L1, PD-L1 blockade increased the glucose concentrations in the extracellular tumor milieu. In a related study, Kleffel et al. showed that PD-1 was present on melanoma cells, that its binding to PD-L1 promoted the growth of melanomas in mice, and that PD-1 blockade decreased melanoma growth in immunocompromised mice. Thus, tumors trigger exhaustion in T cells through metabolic competition, and PD-1 and PD-L1 blockade may decrease aerobic glycolysis in tumors, thereby enhancing the function of TILs (see the commentary by Sukumar et al.).

P.-C. Ho, J. D. Bihuniak, A. N. Macintyre, M. Staron, X. Liu, R. Amezquita, Y.-C. Tsui, G. Cui, G. Micevic, J. C. Perales, S. H. Kleinstein, E. D. Abel, K. L. Insogna, S. Feske, J. W. Locasale, M. W. Bosenberg, J. C. Rathmell, S. M. Kaech, Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015). [PubMed]

C.-H. Chang, J. Qiu, D. O’Sullivan, M. D. Buck, T. Noguchi, J. D. Curtis, Q. Chen, M. Gindin, M. M. Gubin, G. J. W. van der Windt, E. Tonc, R. D. Schreiber, E. J. Pearce, E. L. Pearce, Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015). [PubMed]

S. Kleffel, C. Posch, S. R. Barthel, H. Mueller, C. Schlapbach, E. Guenova, C. P. Elco, N. Lee, V. R. Juneja, Q. Zhan, C. G. Lian, R. Thomi, W. Hoetzenecker, A. Cozzio, R. Dummer, M. C. Mihm Jr., K. T. Flaherty, M. H. Frank, G. F. Murphy, A. H. Sharpe, T. S. Kupper, T. Schatton, Melanoma cell-intrinsic PD-1 receptor functions to promote tumor growth. Cell 162, 1242–1256 (2015). [PubMed]

M. Sukumar, R. Roychoudhuri, N. P. Restifo, Nutrient competition: A new axis of tumor immunosuppression. Cell 162, 1206–1208 (2015). [PubMed]