Abstract
The tumor microenvironment (TME) is a complex biological structure surrounding tumor cells and includes blood vessels, immune cells, fibroblasts, adipocytes, and extracellular matrix (ECM) [1, 2]. These heterogeneous surrounding structures provide nutrients, metabolites, and signaling molecules to provide a cancer-friendly environment. The metabolic interplay between immune cells and cancer cells in the TME is a key feature not only for understanding tumor biology but also for discovering cancer cells' vulnerability. As cancer immunotherapy to treat cancer patients and the use of metabolomics technologies become more and more common [3], the importance of the interplay between cancer cells and immune cells in the TME is emerging with respect to not only cell-to-cell interactions but also metabolic pathways. This interaction between immune cells and cancer cells is a complex and dynamic process in which immune cells act as a determinant factor of cancer cells' fate and vice versa. In this chapter, we provide an overview of the metabolic interplay between immune cells and cancer cells and discuss the therapeutic opportunities as a result of this interplay in order to define targets for cancer treatment. It is important to understand and identify therapeutic targets that interrupt this cancerpromoting relationship between cancer cells and the surrounding immune cells, allowing for maximum efficacy of immune checkpoint inhibitors as well as other genetic and cellular therapies.
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References
- Antonio, M. J., Zhang, C., & Le, A. (2021). Different tumor microenvironments lead to different metabolic phenotypes. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_10 doi: 10.1007/978-3-030-65768-0_10. [DOI] [PMC free article] [PubMed]
- Nabi, K., & Le, A. (2021). The intratumoral heterogeneity of cancer metabolism. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_11 doi: 10.1007/978-3-030-65768-0_11. [DOI] [PMC free article] [PubMed]
- Hoang, G., Udupa, S., & Le, A. (2019). Application of metabolomics technologies toward cancer prognosis and therapy. International Review of Cell and Molecular Biology, 347, 191–223. doi: 10.1016/bs.ircmb.2019.07.003. [DOI] [PubMed]
- Munn, D. H., et al. (2002). Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science, 297(5588), 1867–1870. doi: 10.1126/science.1073514. [DOI] [PubMed]
- Lee, G. K., et al. (2002). Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology, 107(4), 452–460. doi: 10.1046/j.1365-2567.2002.01526.x. [DOI] [PMC free article] [PubMed]
- Rodriguez, P. C., et al. (2004). Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Research, 64(16), 5839–5849. doi: 10.1158/0008-5472.CAN-04-0465. [DOI] [PubMed]
- Uyttenhove, C., et al. (2003). Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nature Medicine, 9(10), 1269–1274. doi: 10.1038/nm934. [DOI] [PubMed]
- Adams, J. L., et al. (2015). Big opportunities for small molecules in immuno-oncology. Nature Reviews. Drug Discovery, 14(9), 603–622. doi: 10.1038/nrd4596. [DOI] [PubMed]
- Mondanelli, G., et al. (2019). Immunoregulatory interplay between arginine and tryptophan metabolism in health and disease. Frontiers in Immunology, 10, 1565. doi: 10.3389/fimmu.2019.01565. [DOI] [PMC free article] [PubMed]
- June, C. H. (2007). Adoptive T cell therapy for cancer in the clinic. The Journal of Clinical Investigation, 117(6), 1466–1476. doi: 10.1172/JCI32446. [DOI] [PMC free article] [PubMed]
- Leen, A. M., Rooney, C. M., & Foster, A. E. (2007). Improving T cell therapy for cancer. Annual Review of Immunology, 25, 243–265. doi: 10.1146/annurev.immunol.25.022106.141527. [DOI] [PubMed]
- Kershaw, M. H., Westwood, J. A., & Darcy, P. K. (2013). Gene-engineered T cells for cancer therapy. Nature Reviews. Cancer, 13(8), 525–541. doi: 10.1038/nrc3565. [DOI] [PubMed]
- Ribas, A. (2015). Adaptive immune resistance: How cancer protects from immune attack. Cancer Discovery, 5(9), 915–919. doi: 10.1158/2159-8290.CD-15-0563. [DOI] [PMC free article] [PubMed]
- Vesely, S., et al. (2013). Parameters derived from the postoperative decline in ultrasensitive PSA improve the prediction of radical prostatectomy outcome. World Journal of Urology, 31(2), 299–304. doi: 10.1007/s00345-012-0892-3. [DOI] [PubMed]
- Cubillos-Ruiz, J. R., et al. (2015). ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell, 161(7), 1527–1538. doi: 10.1016/j.cell.2015.05.025. [DOI] [PMC free article] [PubMed]
- Ramakrishnan, R., et al. (2014). Oxidized lipids block antigen cross-presentation by dendritic cells in cancer. Journal of Immunology, 192(6), 2920–2931. doi: 10.4049/jimmunol.1302801. [DOI] [PMC free article] [PubMed]
- Nieman, K. M., et al. (2011). Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature Medicine, 17(11), 1498–1503. doi: 10.1038/nm.2492. [DOI] [PMC free article] [PubMed]
- Sazeides, C., & Le, A. (2021). Metabolic relationship between cancer-associated fibroblasts and cancer cells. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_14 doi: 10.1007/978-3-030-65768-0_14. [DOI] [PMC free article] [PubMed]
- Jung, J. G., & Le, A. (2021). Targeting metabolic cross talk between cancer cells and cancer associated fibroblasts. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_15 doi: 10.1007/978-3-030-65768-0_15. [DOI] [PMC free article] [PubMed]
- Hsu, Y. L., et al. (2016). Lung cancer-derived galectin-1 contributes to cancer associated fibroblast-mediated cancer progression and immune suppression through TDO2/kynurenine axis. Oncotarget, 7(19), 27584–27598. doi: 10.18632/oncotarget.8488. [DOI] [PMC free article] [PubMed]
- Arcucci, A., et al. (2016). Cancer: An oxidative crosstalk between solid tumor cells and cancer associated fibroblasts. BioMed Research International, 2016, 4502846. doi: 10.1155/2016/4502846. [DOI] [PMC free article] [PubMed]
- Buck, M. D., O’Sullivan, D., & Pearce, E. L. (2015). T cell metabolism drives immunity. The Journal of Experimental Medicine, 212(9), 1345–1360. doi: 10.1084/jem.20151159. [DOI] [PMC free article] [PubMed]
- O’Neill, L. A., & Pearce, E. J. (2016). Immunometabolism governs dendritic cell and macrophage function. The Journal of Experimental Medicine, 213(1), 15–23. doi: 10.1084/jem.20151570. [DOI] [PMC free article] [PubMed]
- Le, A., et al. (2012). Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metabolism, 15(1), 110–121. doi: 10.1016/j.cmet.2011.12.009. [DOI] [PMC free article] [PubMed]
- Pavlova, N. N., & Thompson, C. B. (2016). The emerging hallmarks of cancer metabolism. Cell Metabolism, 23(1), 27–47. doi: 10.1016/j.cmet.2015.12.006. [DOI] [PMC free article] [PubMed]
- Andrejeva, G., & Rathmell, J. C. (2017). Similarities and distinctions of cancer and immune metabolism in inflammation and tumors. Cell Metabolism, 26(1), 49–70. doi: 10.1016/j.cmet.2017.06.004. [DOI] [PMC free article] [PubMed]
- Li, T., Copeland, C., & Le, A. (2021). Glutamine metabolism in cancer. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_2 doi: 10.1007/978-3-030-65768-0_2. [DOI] [PMC free article] [PubMed]
- Jin, L., Alesi, G. N., & Kang, S. (2016). Glutaminolysis as a target for cancer therapy. Oncogene, 35(28), 3619–3625. doi: 10.1038/onc.2015.447. [DOI] [PMC free article] [PubMed]
- Perez-Escuredo, J., et al. (2016). Lactate promotes glutamine uptake and metabolism in oxidative cancer cells. Cell Cycle, 15(1), 72–83. doi: 10.1080/15384101.2015.1120930. [DOI] [PMC free article] [PubMed]
- Swamy, M., et al. (2016). Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy. Nature Immunology, 17(6), 712–720. doi: 10.1038/ni.3439. [DOI] [PMC free article] [PubMed]
- Tyrakis, P. A., et al. (2016). S-2-hydroxyglutarate regulates CD8(+) T-lymphocyte fate. Nature, 540(7632), 236–241. doi: 10.1038/nature20165. [DOI] [PMC free article] [PubMed]
- Wang, Q., et al. (2015). Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development. The Journal of Pathology, 236(3), 278–289. doi: 10.1002/path.4518. [DOI] [PMC free article] [PubMed]
- Fox, C. J., Hammerman, P. S., & Thompson, C. B. (2005). Fuel feeds function: Energy metabolism and the T-cell response. Nature Reviews. Immunology, 5(11), 844–852. doi: 10.1038/nri1710. [DOI] [PubMed]
- Rathmell, J. C., et al. (2001). IL-7 enhances the survival and maintains the size of naive T cells. Journal of Immunology, 167(12), 6869–6876. doi: 10.4049/jimmunol.167.12.6869. [DOI] [PubMed]
- Wofford, J. A., et al. (2008). IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood, 111(4), 2101–2111. doi: 10.1182/blood-2007-06-096297. [DOI] [PMC free article] [PubMed]
- Macintyre, A. N., et al. (2014). The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metabolism, 20(1), 61–72. doi: 10.1016/j.cmet.2014.05.004. [DOI] [PMC free article] [PubMed]
- Blad, C. C., Tang, C., & Offermanns, S. (2012). G protein-coupled receptors for energy metabolites as new therapeutic targets. Nature Reviews. Drug Discovery, 11(8), 603–619. doi: 10.1038/nrd3777. [DOI] [PubMed]
- Rubic, T., et al. (2008). Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nature Immunology, 9(11), 1261–1269. doi: 10.1038/ni.1657. [DOI] [PubMed]
- Csoka, B., et al. (2012). Adenosine promotes alternative macrophage activation via A2A and A2B receptors. The FASEB Journal, 26(1), 376–386. doi: 10.1096/fj.11-190934. [DOI] [PMC free article] [PubMed]
- Kidani, Y., & Bensinger, S. J. (2012). Liver X receptor and peroxisome proliferator-activated receptor as integrators of lipid homeostasis and immunity. Immunological Reviews, 249(1), 72–83. doi: 10.1111/j.1600-065X.2012.01153.x. [DOI] [PMC free article] [PubMed]
- Wang, R., et al. (2011). The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity, 35(6), 871–882. doi: 10.1016/j.immuni.2011.09.021. [DOI] [PMC free article] [PubMed]
- Gerriets, V. A., & Rathmell, J. C. (2012). Metabolic pathways in T cell fate and function. Trends in Immunology, 33(4), 168–173. doi: 10.1016/j.it.2012.01.010. [DOI] [PMC free article] [PubMed]
- Dang, C. V., Le, A., & Gao, P. (2009). MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clinical Cancer Research, 15(21), 6479–6483. doi: 10.1158/1078-0432.CCR-09-0889. [DOI] [PMC free article] [PubMed]
- Le, A., & Dang, C. V. (2013). Studying Myc’s role in metabolism regulation. Methods in Molecular Biology, 1012, 213–219. doi: 10.1007/978-1-62703-429-6_14. [DOI] [PMC free article] [PubMed]
- Frauwirth, K. A., et al. (2002). The CD28 signaling pathway regulates glucose metabolism. Immunity, 16(6), 769–777. doi: 10.1016/s1074-7613(02)00323-0. [DOI] [PubMed]
- Michalek, R. D., et al. (2011). Estrogen-related receptor-alpha is a metabolic regulator of effector T-cell activation and differentiation. Proceedings of the National Academy of Sciences of the United States of America, 108(45), 18348–18353. doi: 10.1073/pnas.1108856108. [DOI] [PMC free article] [PubMed]
- Wang, R., & Green, D. R. (2012). Metabolic checkpoints in activated T cells. Nature Immunology, 13(10), 907–915. doi: 10.1038/ni.2386. [DOI] [PubMed]
- Michalek, R. D., et al. (2011). Cutting edge: Distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. Journal of Immunology, 186(6), 3299–3303. doi: 10.4049/jimmunol.1003613. [DOI] [PMC free article] [PubMed]
- Jacobs, S. R., et al. (2008). Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. Journal of Immunology, 180(7), 4476–4486. doi: 10.4049/jimmunol.180.7.4476. [DOI] [PMC free article] [PubMed]
- Carr, E. L., et al. (2010). Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. Journal of Immunology, 185(2), 1037–1044. doi: 10.4049/jimmunol.0903586. [DOI] [PMC free article] [PubMed]
- Murray, C. M., et al. (2005). Monocarboxylate transporter MCT1 is a target for immunosuppression. Nature Chemical Biology, 1(7), 371–376. doi: 10.1038/nchembio744. [DOI] [PubMed]
- Doedens, A. L., et al. (2013). Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nature Immunology, 14(11), 1173–1182. doi: 10.1038/ni.2714. [DOI] [PMC free article] [PubMed]
- Finlay, D. K., et al. (2012). PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. The Journal of Experimental Medicine, 209(13), 2441–2453. doi: 10.1084/jem.20112607. [DOI] [PMC free article] [PubMed]
- Chou, C., et al. (2014). c-Myc-induced transcription factor AP4 is required for host protection mediated by CD8+ T cells. Nature Immunology, 15(9), 884–893. doi: 10.1038/ni.2943. [DOI] [PMC free article] [PubMed]
- Kim, J. W., et al. (2006). HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metabolism, 3(3), 177–185. doi: 10.1016/j.cmet.2006.02.002. [DOI] [PubMed]
- Papandreou, I., et al. (2006). HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metabolism, 3(3), 187–197. doi: 10.1016/j.cmet.2006.01.012. [DOI] [PubMed]
- Shi, L. Z., et al. (2011). HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. The Journal of Experimental Medicine, 208(7), 1367–1376. doi: 10.1084/jem.20110278. [DOI] [PMC free article] [PubMed]
- Harty, J. T., & Badovinac, V. P. (2008). Shaping and reshaping CD8+ T-cell memory. Nature Reviews. Immunology, 8(2), 107–119. doi: 10.1038/nri2251. [DOI] [PubMed]
- Rosenblum, M. D., Way, S. S., & Abbas, A. K. (2016). Regulatory T cell memory. Nature Reviews. Immunology, 16(2), 90–101. doi: 10.1038/nri.2015.1. [DOI] [PMC free article] [PubMed]
- van der Windt, G. J., & Pearce, E. L. (2012). Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunological Reviews, 249(1), 27–42. doi: 10.1111/j.1600-065X.2012.01150.x. [DOI] [PMC free article] [PubMed]
- Crespo, J., et al. (2013). T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Current Opinion in Immunology, 25(2), 214–221. doi: 10.1016/j.coi.2012.12.003. [DOI] [PMC free article] [PubMed]
- Munn, D. H., & Mellor, A. L. (2013). Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends in Immunology, 34(3), 137–143. doi: 10.1016/j.it.2012.10.001. [DOI] [PMC free article] [PubMed]
- Munn, D. H., et al. (1999). Inhibition of T cell proliferation by macrophage tryptophan catabolism. The Journal of Experimental Medicine, 189(9), 1363–1372. doi: 10.1084/jem.189.9.1363. [DOI] [PMC free article] [PubMed]
- Fischer, K., et al. (2007). Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood, 109(9), 3812–3819. doi: 10.1182/blood-2006-07-035972. [DOI] [PubMed]
- Cham, C. M., et al. (2008). Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8+ T cells. European Journal of Immunology, 38(9), 2438–2450. doi: 10.1002/eji.200838289. [DOI] [PMC free article] [PubMed]
- Bose, S., Zhang, C., & Le, A. (2021). Glucose metabolism in cancer: The Warburg effect and beyond. Advances in Experimental Medicine and Biology, 1311, https://doi.org/10.1007/978-3-030-65768-0_1 doi: 10.1007/978-3-030-65768-0_1. [DOI] [PMC free article] [PubMed]
- Gatenby, R. A., & Gillies, R. J. (2004). Why do cancers have high aerobic glycolysis? Nature Reviews. Cancer, 4(11), 891–899. doi: 10.1038/nrc1478. [DOI] [PubMed]
- Warburg, O. (1956). On the origin of cancer cells. Science, 123(3191), 309–314. doi: 10.1126/science.123.3191.309. [DOI] [PubMed]
- Chang, C. H., et al. (2015). Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell, 162(6), 1229–1241. doi: 10.1016/j.cell.2015.08.016. [DOI] [PMC free article] [PubMed]
- Ho, P. C., et al. (2015). Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell, 162(6), 1217–1228. doi: 10.1016/j.cell.2015.08.012. [DOI] [PMC free article] [PubMed]
- Sugiura, A., & Rathmell, J. C. (2018). Metabolic barriers to T cell function in tumors. Journal of Immunology, 200(2), 400–407. doi: 10.4049/jimmunol.1701041. [DOI] [PMC free article] [PubMed]
- D’Aloia, M. M., et al. (2018). CAR-T cells: The long and winding road to solid tumors. Cell Death & Disease, 9(3), 282. doi: 10.1038/s41419-018-0278-6. [DOI] [PMC free article] [PubMed]
- Mikucki, M. E., et al. (2015). Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nature Communications, 6, 7458. doi: 10.1038/ncomms8458. [DOI] [PMC free article] [PubMed]
- Stewart, M. D., & Sanderson, R. D. (2014). Heparan sulfate in the nucleus and its control of cellular functions. Matrix Biology, 35, 56–59. doi: 10.1016/j.matbio.2013.10.009. [DOI] [PMC free article] [PubMed]
- Caruana, I., et al. (2015). Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nature Medicine, 21(5), 524–529. doi: 10.1038/nm.3833. [DOI] [PMC free article] [PubMed]
- Tahmasebi, S., Elahi, R., & Esmaeilzadeh, A. (2019). Solid tumors challenges and new insights of CAR T cell engineering. Stem Cell Reviews and Reports, 15(5), 619–636. doi: 10.1007/s12015-019-09901-7. [DOI] [PubMed]
- Wang, L. C., et al. (2014). Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunology Research, 2(2), 154–166. doi: 10.1158/2326-6066.CIR-13-0027. [DOI] [PMC free article] [PubMed]
- Nishio, N., & Dotti, G. (2015). Oncolytic virus expressing RANTES and IL-15 enhances function of CAR-modified T cells in solid tumors. Oncoimmunology, 4(2), e988098. doi: 10.4161/21505594.2014.988098. [DOI] [PMC free article] [PubMed]
- Whilding, L. M., et al. (2019). CAR T-cells targeting the integrin alphavbeta6 and co-expressing the chemokine receptor CXCR2 demonstrate enhanced homing and efficacy against several solid malignancies. Cancers (Basel), 11, 5. doi: 10.3390/cancers11050674. [DOI] [PMC free article] [PubMed]
- Hosen, N., et al. (2017). The activated conformation of integrin beta7 is a novel multiple myeloma-specific target for CAR T cell therapy. Nature Medicine, 23(12), 1436–1443. doi: 10.1038/nm.4431. [DOI] [PubMed]
- Posey, A. D., Jr., et al. (2016). Engineered CAR T cells targeting the cancer-associated Tn-glycoform of the membrane mucin MUC1 control adenocarcinoma. Immunity, 44(6), 1444–1454. doi: 10.1016/j.immuni.2016.05.014. [DOI] [PMC free article] [PubMed]
- Zhou, R., et al. (2019). CAR T cells targeting the tumor MUC1 glycoprotein reduce triple-negative breast cancer growth. Frontiers in Immunology, 10, 1149. doi: 10.3389/fimmu.2019.01149. [DOI] [PMC free article] [PubMed]
- Koneru, M., et al. (2015). IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology, 4(3), e994446. doi: 10.4161/2162402X.2014.994446. [DOI] [PMC free article] [PubMed]
- Zhang, L., et al. (2013). Inhibition of TGF-beta signaling in genetically engineered tumor antigen-reactive T cells significantly enhances tumor treatment efficacy. Gene Therapy, 20(5), 575–580. doi: 10.1038/gt.2012.75. [DOI] [PMC free article] [PubMed]
- Mohammed, S., et al. (2017). Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. Molecular Therapy, 25(1), 249–258. doi: 10.1016/j.ymthe.2016.10.016. [DOI] [PMC free article] [PubMed]
- Adachi, K., et al. (2018). IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nature Biotechnology, 36(4), 346–351. doi: 10.1038/nbt.4086. [DOI] [PubMed]
- Arab, S., & Hadjati, J. (2019). Adenosine blockage in tumor microenvironment and improvement of cancer immunotherapy. Immune Network, 19(4), e23. doi: 10.4110/in.2019.19.e23. [DOI] [PMC free article] [PubMed]
- Beavis, P. A., et al. (2017). Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy. The Journal of Clinical Investigation, 127(3), 929–941. doi: 10.1172/JCI89455. [DOI] [PMC free article] [PubMed]
- Srivastava, S., & Riddell, S. R. (2018). Chimeric antigen receptor T cell therapy: Challenges to bench-to-bedside efficacy. Journal of Immunology, 200(2), 459–468. doi: 10.4049/jimmunol.1701155. [DOI] [PMC free article] [PubMed]
- Arab, S., et al. (2017). Increased efficacy of a dendritic cell-based therapeutic cancer vaccine with adenosine receptor antagonist and CD73 inhibitor. Tumour Biology, 39(3), 1010428317695021. doi: 10.1177/1010428317695021. [DOI] [PubMed]
- Ligtenberg, M. A., et al. (2016). Coexpressed catalase protects chimeric antigen receptor-redirected T cells as well as bystander cells from oxidative stress-induced loss of antitumor activity. Journal of Immunology, 196(2), 759–766. doi: 10.4049/jimmunol.1401710. [DOI] [PMC free article] [PubMed]
- Ninomiya, S., et al. (2015). Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs. Blood, 125(25), 3905–3916. doi: 10.1182/blood-2015-01-621474. [DOI] [PMC free article] [PubMed]
- Newick, K., Moon, E., & Albelda, S. M. (2016). Chimeric antigen receptor T-cell therapy for solid tumors. Molecular Therapy Oncolytics, 3, 16006. doi: 10.1038/mto.2016.6. [DOI] [PMC free article] [PubMed]
- Scheffel, M. J., et al. (2016). Efficacy of adoptive T-cell therapy is improved by treatment with the antioxidant N-acetyl cysteine, which limits activation-induced T-cell death. Cancer Research, 76(20), 6006–6016. doi: 10.1158/0008-5472.CAN-16-0587. [DOI] [PMC free article] [PubMed]
- Peggs, K. S., et al. (2009). Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. The Journal of Experimental Medicine, 206(8), 1717–1725. doi: 10.1084/jem.20082492. [DOI] [PMC free article] [PubMed]
- Ren, J., et al. (2017). A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget, 8(10), 17002–17011. doi: 10.18632/oncotarget.15218. [DOI] [PMC free article] [PubMed]
- John, L. B., et al. (2013). Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clinical Cancer Research, 19(20), 5636–5646. doi: 10.1158/1078-0432.CCR-13-0458. [DOI] [PubMed]
- Rupp, L. J., et al. (2017). CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Scientific Reports, 7(1), 737. doi: 10.1038/s41598-017-00462-8. [DOI] [PMC free article] [PubMed]
- Liu, X., et al. (2016). A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Research, 76(6), 1578–1590. doi: 10.1158/0008-5472.CAN-15-2524. [DOI] [PMC free article] [PubMed]
- Yoon, D. H., et al. (2018). Incorporation of immune checkpoint blockade into chimeric antigen receptor T cells (CAR-Ts): Combination or built-In CAR-T. International Journal of Molecular Sciences, 19, 2. doi: 10.3390/ijms19020340. [DOI] [PMC free article] [PubMed]
- Fourcade, J., et al. (2012). CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Research, 72(4), 887–896. doi: 10.1158/0008-5472.CAN-11-2637. [DOI] [PMC free article] [PubMed]
- Boice, M., et al. (2016). Loss of the HVEM tumor suppressor in lymphoma and restoration by modified CAR-T cells. Cell, 167(2), 405–418. e13. doi: 10.1016/j.cell.2016.08.032. [DOI] [PMC free article] [PubMed]
- Johnston, R. J., Yu, X., & Grogan, J. L. (2015). The checkpoint inhibitor TIGIT limits antitumor and antiviral CD8(+) T cell responses. Oncoimmunology, 4(9), e1036214. doi: 10.1080/2162402X.2015.1036214. [DOI] [PMC free article] [PubMed]
- Kuhn, N. F., et al. (2019). CD40 ligand-modified chimeric antigen receptor T cells enhance antitumor function by eliciting an endogenous antitumor response. Cancer Cell, 35(3), 473–488. e6. doi: 10.1016/j.ccell.2019.02.006. [DOI] [PMC free article] [PubMed]
- Kershaw, M. H., et al. (2002). Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. Human Gene Therapy, 13(16), 1971–1980. doi: 10.1089/10430340260355374. [DOI] [PubMed]
- Long, A. H., et al. (2016). Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas. Cancer Immunology Research, 4(10), 869–880. doi: 10.1158/2326-6066.CIR-15-0230. [DOI] [PMC free article] [PubMed]
- Zhou, Q., et al. (2010). Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood, 116(14), 2484–2493. doi: 10.1182/blood-2010-03-275446. [DOI] [PMC free article] [PubMed]
- Markley, J. C., & Sadelain, M. (2010). IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell-mediated rejection of systemic lymphoma in immunodeficient mice. Blood, 115(17), 3508–3519. doi: 10.1182/blood-2009-09-241398. [DOI] [PMC free article] [PubMed]
- Yao, X., et al. (2012). Levels of peripheral CD4(+)FoxP3(+) regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood, 119(24), 5688–5696. doi: 10.1182/blood-2011-10-386482. [DOI] [PMC free article] [PubMed]
- Spear, P., et al. (2012). Chimeric antigen receptor T cells shape myeloid cell function within the tumor microenvironment through IFN-gamma and GM-CSF. Journal of Immunology, 188(12), 6389–6398. doi: 10.4049/jimmunol.1103019. [DOI] [PMC free article] [PubMed]
- Chmielewski, M., & Abken, H. (2017). CAR T cells releasing IL-18 convert to T-Bet(high) FoxO1(low) effectors that exhibit augmented activity against advanced solid tumors. Cell Reports, 21(11), 3205–3219. doi: 10.1016/j.celrep.2017.11.063. [DOI] [PubMed]
- Clever, D., et al. (2016). Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell, 166(5), 1117–1131. e14. doi: 10.1016/j.cell.2016.07.032. [DOI] [PMC free article] [PubMed]
- Scharping, N. E., et al. (2016). The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity, 45(2), 374–388. doi: 10.1016/j.immuni.2016.07.009. [DOI] [PMC free article] [PubMed]
- Wherry, E. J., & Kurachi, M. (2015). Molecular and cellular insights into T cell exhaustion. Nature Reviews. Immunology, 15(8), 486–499. doi: 10.1038/nri3862. [DOI] [PMC free article] [PubMed]
- Vaddepally, R. K., et al. (2020). Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers (Basel), 12, 3. doi: 10.3390/cancers12030738. [DOI] [PMC free article] [PubMed]
- Chang, K. C., et al. (2013). Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis. Critical Care, 17(3), R85. doi: 10.1186/cc12711. [DOI] [PMC free article] [PubMed]
- Bengsch, B., et al. (2016). Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8(+) T cell exhaustion. Immunity, 45(2), 358–373. doi: 10.1016/j.immuni.2016.07.008. [DOI] [PMC free article] [PubMed]
- Parry, R. V., et al. (2005). CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Molecular and Cellular Biology, 25(21), 9543–9553. doi: 10.1128/MCB.25.21.9543-9553.2005. [DOI] [PMC free article] [PubMed]
- Patsoukis, N., et al. (2015). PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nature Communications, 6, 6692. doi: 10.1038/ncomms7692. [DOI] [PMC free article] [PubMed]
- Riley, J. L. (2009). PD-1 signaling in primary T cells. Immunological Reviews, 229(1), 114–125. doi: 10.1111/j.1600-065X.2009.00767.x. [DOI] [PMC free article] [PubMed]
- Kleffel, S., et al. (2015). Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell, 162(6), 1242–1256. doi: 10.1016/j.cell.2015.08.052. [DOI] [PMC free article] [PubMed]
- Staron, M. M., et al. (2014). The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T cells during chronic infection. Immunity, 41(5), 802–814. doi: 10.1016/j.immuni.2014.10.013. [DOI] [PMC free article] [PubMed]
- Ma, S., et al. (2019). Current progress in CAR-T cell therapy for solid tumors. International Journal of Biological Sciences, 15(12), 2548–2560. doi: 10.7150/ijbs.34213. [DOI] [PMC free article] [PubMed]
- Juillerat, A., et al. (2017). An oxygen sensitive self-decision making engineered CAR T-cell. Scientific Reports, 7, 39833. doi: 10.1038/srep39833. [DOI] [PMC free article] [PubMed]
- Petersen, C. T., & Krenciute, G. (2019). Next generation CAR T cells for the immunotherapy of high-grade glioma. Frontiers in Oncology, 9, 69. doi: 10.3389/fonc.2019.00069. [DOI] [PMC free article] [PubMed]
- Dwyer, C. J., et al. (2019). Fueling cancer immunotherapy with common gamma chain cytokines. Frontiers in Immunology, 10, 263. doi: 10.3389/fimmu.2019.00263. [DOI] [PMC free article] [PubMed]
- Gomez-Eerland, R., et al. (2014). Manufacture of gene-modified human T-cells with a memory stem/central memory phenotype. Human Gene Therapy Methods, 25(5), 277–287. doi: 10.1089/hgtb.2014.004. [DOI] [PMC free article] [PubMed]
- Eil, R., et al. (2016). Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature, 537(7621), 539–543. doi: 10.1038/nature19364. [DOI] [PMC free article] [PubMed]
