Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy

Cancer Cell

Volumn 32, Issue 3, 2017, Pages 377-391.e9

  Zhang, Ying ^a,b,h   Kurupati, Raj ^b   Liu, Ling ^c   Zhou, Xiang Yang ^b   Zhang, Gao ^b   Hudaihed, Abeer ^d   Filisio, Flavia ^d   Giles Davis, Wynetta ^b   Xu, Xiaowei ^e   Karakousis, Giorgos C ^f   Schuchter, Lynn M ^e   Xu, Wei ^e   Amaravadi, Ravi ^e   Xiao, Min ^b   Sadek, Norah ^b   Krepler, Clemens ^b   Herlyn, Meenhard ^b   Freeman, Gordon J ^g   Rabinowitz, Joshua D ^c   Ertl, Hildegund C J ^b  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b WISTAR INSTITUTE   (United States)

^c PRINCETON UNIVERSITY   (United States)

^d TEMPLE UNIVERSITY   (United States)

^e Department of Neuroscience   (United States)

^f HOSPITAL OF THE UNIVERSITY OF PENNSYLVANIA   (United States)

^g DANA FARBER CANCER INSTITUTE   (United States)

^h BOSTON CHILDREN S HOSPITAL   (United States)

Author keywords

CD8+ T cells; co inhibitors; fatty acid catabolism; fenofibrate; HIF 1 ; hypoglycemia; hypoxia; melanoma; TILs; tumor microenvironment

Indexed keywords

FATTY ACID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PROGRAMMED DEATH 1 RECEPTOR; CD223 ANTIGEN; GLUCOSE; HIF1A PROTEIN, HUMAN; HYPOXIA INDUCIBLE FACTOR 1ALPHA; LEUKOCYTE ANTIGEN; OXYGEN; PDCD1 PROTEIN, HUMAN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIGEN SPECIFICITY; ARTICLE; CANCER IMMUNOTHERAPY; CANCER INHIBITION; CD8+ T LYMPHOCYTE; CONTROLLED STUDY; EFFECTOR CELL; GENE EXPRESSION; HYPOGLYCEMIA; HYPOXIA; LIPOLYSIS; LYMPHOCYTE FUNCTION; MELANOMA; MOUSE; NONHUMAN; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; TUMOR ASSOCIATED LEUKOCYTE; TUMOR MICROENVIRONMENT; ANIMAL; C57BL MOUSE; CELL HYPOXIA; DISEASE COURSE; FEMALE; GENE SILENCING; HUMAN; IMMUNOLOGY; IMMUNOTHERAPY; LYMPHOCYTE ACTIVATION; METABOLISM; PATHOLOGY; PHYSIOLOGICAL STRESS; TREATMENT OUTCOME; ULTRASTRUCTURE;

ANIMALS; ANTIGENS, CD; CD8-POSITIVE T-LYMPHOCYTES; CELL HYPOXIA; DISEASE PROGRESSION; FATTY ACIDS; FEMALE; GENE KNOCKDOWN TECHNIQUES; GLUCOSE; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT; IMMUNOTHERAPY; LYMPHOCYTE ACTIVATION; LYMPHOCYTES, TUMOR-INFILTRATING; MELANOMA; MICE, INBRED C57BL; OXYGEN; PROGRAMMED CELL DEATH 1 RECEPTOR; STRESS, PHYSIOLOGICAL; TREATMENT OUTCOME; TUMOR MICROENVIRONMENT;

EID: 85030419289     PISSN: 15356108     EISSN: 18783686     Source Type: Journal    
DOI: 10.1016/j.ccell.2017.08.004     Document Type: Article

References (37)

1. Azuma, T., Yao, S., Zhu, G., Flies, A.S., Flies, S.J., Chen, L., B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood 111 (2008), 3635–3643.
2. Balmer, M.L., Ma, E.H., Bantug, G.R., Grählert, J., Pfister, S., Glatter, T., Jauch, A., Dimeloe, S., Slack, E., Dehio, P., et al. Memory CD8+ T cells require increased concentrations of acetate induced by stress for optimal function. Immunity 44 (2016), 1312–1324.
3. Bucks, C.M., Norton, J.A., Boesteanu, A.C., Mueller, Y.M., Katsikis, P.D., Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion. J. Immunol. 182 (2009), 6697–6708.
4. Chamoto, K., Chowdhury, P.S., Kumar, A., Sonomura, K., Matsuda, F., Fagarasan, S., Honjo, T., Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proc. Natl. Acad. Sci. USA 114 (2017), E761–E770.
5. Chang, C.-H., Qiu, J., O'Sullivan, D., Buck, M.D., Noguchi, T., Curtis, J.D., Chen, Q., Gindin, M., Gubin, M.M., van der Windt, G.J.W., et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell, 2015, 10.1016/j.cell.2015.08.016.
6. Chen, L., Han, X., Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J. Clin. Invest. 125 (2015), 3384–3391.
7. Crompton, J.G., Sukumar, M., Roychoudhuri, R., Clever, D., Gros, A., Eil, R.L., Tran, E., Hanada, K.I., Yu, Z., Palmer, D.C., et al. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res. 75 (2015), 296–305.
8. Dalgleish, A.G., Therapeutic cancer vaccines: why so few randomised phase III studies reflect the initial optimism of phase II studies. Vaccine 29 (2011), 8501–8505.
9. Doedens, A.L., Phan, A.T., Stradner, M.H., Fujimoto, J.K., Nguyen, J.V., Yang, E., Johnson, R.S., Goldrath, A.W., Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat. Immunol. 14 (2013), 1173–1182.
10. Finlay, D.K., Rosenzweig, E., Sinclair, L.V., Feijoo-Carnero, C., Hukelmann, J.L., Rolf, J., Panteleyev, A.A., Okkenhaug, K., Cantrell, D.A., PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Cell Biol., 199, 2012, i8.
11. Grosso, J.F., Kelleher, C.C., Harris, T.J., Maris, C.H., Hipkiss, E.L., De Marzo, A., Anders, R., Netto, G., Getnet, D., Bruno, T.C., et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J. Clin. Invest. 117 (2007), 3383–3392.
12. Hamanaka, R.B., Chandel, N.S., Targeting glucose metabolism for cancer therapy. J. Exp. Med. 209 (2012), 211–215.
13. Hamid, O., Robert, C., Daud, A., Hodi, F.S., Hwu, W.-J., Kefford, R., Wolchok, J.D., Hersey, P., Joseph, R.W., Weber, J.S., et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369 (2013), 134–144.
14. Ho, P.-C., Bihuniak, J.D., Macintyre, A.N., Staron, M., Liu, X., Amezquita, R., Tsui, Y.-C., Cui, G., Micevic, G., Perales, J.C., et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162 (2015), 1217–1228.
15. Kaech, S.M., Cui, W., Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol. 12 (2012), 749–761.
16. Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J.-J., Cowey, C.L., Lao, C.D., Schadendorf, D., Dummer, R., Smylie, M., Rutkowski, P., et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373 (2015), 23–34.
17. Lasaro, M.O., Tatsis, N., Hensley, S.E., Whitbeck, J.C., Lin, S.-W., Rux, J.J., Wherry, E.J., Cohen, G.H., Eisenberg, R.J., Ertl, H.C., Targeting of antigen to the herpesvirus entry mediator augments primary adaptive immune responses. Nat. Med. 14 (2008), 205–212.
18. Lu, W., Clasquin, M.F., Melamud, E., Amador-Noguez, D., Caudy, A.A., Rabinowitz, J.D., Metabolomic analysis via reversed-phase ion-pairing liquid chromatography coupled to a stand alone orbitrap mass spectrometer. Anal. Chem. 82 (2010), 3212–3221.
19. Martinez-Outschoorn, U.E., Lin, Z., Whitaker-Menezes, D., Howell, A., Sotgia, F., Lisanti, M.P., Ketone body utilization drives tumor growth and metastasis. Cell Cycle 11 (2012), 3964–3971.
20. McNamee, E.N., Korns Johnson, D., Homann, D., Clambey, E.T., Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function. Immunol. Res. 55 (2013), 58–70.
21. Menendez, J.A., Lupu, R., Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 7 (2007), 763–777.
22. Mrass, P., Takano, H., Ng, L.G., Daxini, S., Lasaro, M.O., Iparraguirre, A., Cavanagh, L.L., von Andrian, U.H., Ertl, H.C.J., Haydon, P.G., Weninger, W., Random migration precedes stable target cell interactions of tumor-infiltrating T cells. J. Exp. Med. 203 (2006), 2749–2761.
23. Mueller, S.N., Ahmed, R., High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc. Natl. Acad. Sci. USA 106 (2009), 8623–8628.
24. O'Sullivan, D., van der Windt, G.J.W., Huang, S.C.-C., Curtis, J.D., Chang, C.-H., Buck, M.D., Qiu, J., Smith, A.M., Lam, W.Y., DiPlato, L.M., et al. Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41 (2014), 75–88.
25. Ohta, A., Diwanji, R., Kini, R., Subramanian, M., Ohta, A., Sitkovsky, M., In vivo T cell activation in lymphoid tissues is inhibited in the oxygen-poor microenvironment. Front. Immunol., 2, 2011, 27.
26. Parry, R.V., Chemnitz, J.M., Frauwirth, K.A., Lanfranco, A.R., Braunstein, I., Kobayashi, S.V., Linsley, P.S., Thompson, C.B., Riley, J.L., CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25 (2005), 9543–9553.
27. Patsoukis, N., Bardhan, K., Chatterjee, P., Sari, D., Liu, B., Bell, L.N., Karoly, E.D., Freeman, G.J., Petkova, V., Seth, P., et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat. Commun., 6, 2015, 6692.
28. Patsoukis, N., Li, L., Sari, D., Petkova, V., Boussiotis, V.A., PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2. Mol. Cell. Biol. 33 (2013), 3091–3098.
29. Siska, P.J., Beckermann, K.E., Mason, F.M., Andrejeva, G., Greenplate, A.R., Sendor, A.B., Chiang, Y.-C.J., Corona, A.L., Gemta, L.F., Vincent, B.G., et al. Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight, 2, 2017, 10.1172/jci.insight.93411.
30. Sukumar, M., Liu, J., Ji, Y., Subramanian, M., Crompton, J.G., Yu, Z., Roychoudhuri, R., Palmer, D.C., Muranski, P., Karoly, E.D., et al. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J. Clin. Invest. 123 (2013), 4479–4488.
31. Takahashi, S., Iizumi, T., Mashima, K., Abe, T., Suzuki, N., Roles and regulation of ketogenesis in cultured astroglia and neurons under hypoxia and hypoglycemia. ASN Neuro, 6, 2014, 10.1177/1759091414550997.
32. Tatsis, N., Fitzgerald, J.C., Reyes-Sandoval, A., Harris-McCoy, K.C., Hensley, S.E., Zhou, D., Lin, S.-W., Bian, A., Xiang, Z.Q., Iparraguirre, A., et al. Adenoviral vectors persist in vivo and maintain activated CD8+ T cells: implications for their use as vaccines. Blood 110 (2007), 1916–1923.
33. Veech, R.L., The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot. Essent. Fatty Acids 70 (2004), 309–319.
34. Wiig, H., Aukland, K., Tenstad, O., Isolation of interstitial fluid from rat mammary tumors by a centrifugation method. Am. J. Physiol. Heart Circ. Physiol. 284 (2003), H416–H424.
35. Zhang, Y., Ertl, H.C.J., The effect of adjuvanting cancer vaccines with herpes simplex virus glycoprotein D on melanoma-driven CD8+ T cell exhaustion. J. Immunol. 193 (2014), 1836–1846.
36. Zhu, Y., Ju, S., Chen, E., Dai, S., Li, C., Morel, P., Liu, L., Zhang, X., Lu, B., T-bet and eomesodermin are required for T cell-mediated antitumor immune responses. J. Immunol. 185 (2010), 3174–3183.
37. Zou, W., Wolchok, J.D., Chen, L., PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci. Transl. Med., 8, 2016, 328rv4.