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Review

Tumor-infiltrating lymphocytes for adoptive cell therapy: recent advances, challenges, and future directions

ORCID Icon, , ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 627-641 | Received 26 Jan 2022, Accepted 07 Apr 2022, Published online: 20 Apr 2022

References

  • Rosenberg SA, Yannelli JR, Yang JC, et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst. 1994;86:1159–1166
  • Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298:850–854.
  • Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988;319:1676–1680.
  • Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23:2346–2357.
  • Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17:4550–4557.
  • Rosenberg SA, Dudley ME. Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes. Proc Natl Acad Sci U S A. 2004;101:14639–14645.
  • Schoenfeld AJ, Hellmann MD. Acquired Resistance to Immune Checkpoint Inhibitors. Cancer Cell. 2020;37(4):443–455.
  • Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-Year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381:1535–1546.
  • Sarnaik AA, Hamid O, Khushalani NI, et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol. 2021;39:2656–2666.
  • Creelan BC, Wang C, Teer JK, et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nat Med. 2021;27:1410–1418.
  • Andersen R, Borch TH, Draghi A, et al. T cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression. Ann Oncol. 2018;29:1575–1581.
  • Zacharakis N, Chinnasamy H, Black M, et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat Med. 2018;24:724–730.
  • Met Ö, Jensen KM, Chamberlain CA, et al. Principles of adoptive T cell therapy in cancer. Semin Immunopathol. 2019;41:49–58.
  • Dudley ME, Wunderlich JR, Shelton TE, et al. Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother. 2003;26:332–342.
  • Tran KQ, Zhou J, Durflinger KH, et al. Minimally cultured tumor-infiltrating lymphocytes display optimal characteristics for adoptive cell therapy. J Immunother. 2008;31:742–751.
  • Besser MJ, Shapira-Frommer R, Treves AJ, et al. Minimally cultured or selected autologous tumor-infiltrating lymphocytes after a lympho-depleting chemotherapy regimen in metastatic melanoma patients. J Immunother. 2009;32:415–423.
  • Donia M, Junker N, Ellebaek E, et al. Characterization and comparison of “standard” and “young” tumour-infiltrating lymphocytes for adoptive cell therapy at a danish translational research institution. Scand J Immunol. 2012;75:157–167.
  • Kverneland AH, Borch TH, Granhøj J, et al. Bone marrow toxicity and immune reconstitution in melanoma and non-melanoma solid cancer patients after non-myeloablative conditioning with chemotherapy and checkpoint inhibition. Cytotherapy. 2021;23:724–729.
  • Nguyen LT, Saibil SD, Sotov V, et al. Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2. Cancer Immunol Immunother. 2019;68:773–785.
  • Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic melanoma: Evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26:5233–5239.
  • Yao X, Ahmadzadeh M, Lu YC, et al. Levels of peripheral CD4 +FoxP3 + regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood. 2012;119:5688–5696.
  • Gattinoni L, Finkelstein SE, Klebanoff CA, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005;202:907–912.
  • Klebanoff CA, Khong HT, Antony PA, et al. Sinks, suppressors and antigen presenters: How lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 2005;26:111–117.
  • Jiang T, Zhou C, Ren S. Role of IL-2 in cancer immunotherapy. Oncoimmunology. 2016;5:1–10.
  • Clemente CG, Mihm MC, Bufalino R, et al. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer. 1996;77:1303–1310.
  • Pilon-Thomas S, Kuhn L, Ellwanger S, et al. Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma. J Immunother. 2012;35:615–620.
  • Ellebaek E, Iversen TZ, Junker N, et al. Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients. J Transl Med. 2012;10:1–12.
  • Andersen R, Donia M, Ellebaek E, et al. Long-Lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumor-infiltrating lymphocytes and an attenuated il2 regimen. Clin Cancer Res. 2016;22:3734–3745.
  • Rohaan MW, Van Den Berg JH, Kvistborg P, et al. Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option 11 medical and health sciences 1107 immunology 11 medical and health sciences 1112 oncology and carcinogenesis. J Immunother Cancer. 2018;6:1–16.
  • Davis LE, Shalin SC, Tackett AJ. Current state of melanoma diagnosis and treatment. Cancer Biol Ther. 2019;20:1366–1379.
  • Grimaldi AM, Simeone E, Festino L, et al. MEK inhibitors in the treatment of metastatic melanoma and solid tumors. Am J Clin Dermatol. 2017;18:745–754.
  • Seitter SJ, Sherry RM, Yang JC, et al. Impact of prior treatment on the efficacy of adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma. Clin Cancer Res. 2021;27(19):5289–5298.
  • Borch TH, Andersen R, Ellebaek E, et al. Future role for adoptive T-cell therapy in checkpoint inhibitor-resistant metastatic melanoma. J Immunother Cancer. 2020;8:1–7.
  • Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348:62–68.
  • Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A. 2005;102:18538–18543.
  • Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31:860–867.
  • Nielsen M, Krarup-Hansen A, Hovgaard D, et al. In vitro 4-1BB stimulation promotes expansion of CD8+ tumor-infiltrating lymphocytes from various sarcoma subtypes. Cancer Immunol Immunother. 2020;69:2179–2191.
  • Andersen R, Donia M, Westergaard MCW, et al. Tumor infiltrating lymphocyte therapy for ovarian cancer and renal cell carcinoma. Hum Vaccines Immunother. 2015;11:2790–2795.
  • Junker N, Andersen MH, Wenandy L, et al. Bimodal ex vivo expansion of T cells from patients with head and neck squamous cell carcinoma: a prerequisite for adoptive cell transfer. Cytotherapy. 2011;13:822–834.
  • Yunger S, Bar El A, At ZL, et al. Tumor-infiltrating lymphocytes from human prostate tumors reveal anti-tumor reactivity and potential for adoptive cell therapy. Oncoimmunology. 2019;8.
  • Ben-Avi R, Farhi R, Ben-Nun A, et al. Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients. Cancer Immunol Immunother. 2018;67:1221–1230.
  • Hall ML, Liu H, Malafa M, et al. Expansion of tumor-infiltrating lymphocytes (TIL) from human pancreatic tumors. J Immunother Cancer. 2016;4:1–12.
  • Aydin AM, Hall M, Bunch BL, et al. Expansion of tumor-infiltrating lymphocytes (TIL) from penile cancer patients. Int Immunopharmacol. 2021;94. DOI: https://doi.org/10.1016/j.intimp.2021.107481.
  • Andersen R, Westergaard MCW, Kjeldsen JW, et al. T-cell responses in the microenvironment of primary renal cell carcinoma-Implications for adoptive cell therapy. Cancer Immunol Res. 2018;6:222–235.
  • Westergaard MCW, Andersen R, Chong C, et al. Tumour-reactive T cell subsets in the microenvironment of ovarian cancer. Br J Cancer. 2019;120:424–434.
  • Kverneland AH, Chamberlain CA, Borch TH, et al. Adoptive cell therapy with tumor-infiltrating lymphocytes supported by checkpoint inhibition across multiple solid cancer types. J Immunother Cancer. 2021;9:1–11.
  • Kverneland AH, Pedersen M, Wulff Westergaard MC, et al. Adoptive cell therapy in combination with checkpoint inhibitors in ovarian cancer. Oncotarget. 2020;11:2092–2105.
  • Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014;344:641–645.
  • Gokuldass A, Draghi A, Papp K, et al. Qualitative analysis of tumor-infiltrating lymphocytes across human tumor types reveals a higher proportion of bystander CD8+ T cells in non-melanoma cancers compared to melanoma. Cancers (Basel). 2020;12:1–15.
  • Friese C, Harbst K, Borch TH, et al. CTLA-4 blockade boosts the expansion of tumor-reactive CD8 + tumor-infiltrating lymphocytes in ovarian cancer. Sci Rep. 2020;10. DOI: https://doi.org/10.1038/s41598-019-56089-4
  • Stevanović S, Draper LM, Langhan MM, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol. 2015;33:1543–1550.
  • Tran E, Robbins PF, Y-C L, et al. T-cell transfer therapy targeting mutant kras in cancer. N Engl J Med. 2016;375:2255–2262.
  • Qin SS, Melucci AD, Chacon AC, et al. Adoptive t cell therapy for solid tumors: Pathway to personalized standard of care. Cells. 2021;10. DOI: https://doi.org/10.3390/cells10040808.
  • Sharma P, Hu-Lieskovan S, Wargo JA, et al. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168:707–723.
  • Bashash D, Zandi Z, Kashani B, et al. Resistance to immunotherapy in human malignancies: Mechanisms, research progresses, challenges, and opportunities. J Cell Physiol. 2021.
  • Yeh S, Karne NK, Kerkar SP, et al. Ocular and systemic autoimmunity after successful tumor-infiltrating lymphocyte immunotherapy for recurrent, metastatic melanoma. Ophthalmology. 2009;116:981–989.
  • Yang JC. Toxicities associated with adoptive t-cell transfer for cancer. Cancer J (United States). 2015;21:506–509.
  • Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188–195.
  • Simoni Y, Becht E, Fehlings M, et al. Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature. 2018;557:575–579.
  • Scheper W, Kelderman S, Fanchi LF, et al. Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers. Nat Med. 2019;25:89–94.
  • Gokuldass A, Schina A, Lauss M, et al. Transcriptomic signatures of tumors undergoing T cell attack. Cancer Immunol Immunother. 2021.
  • Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515:577–581.
  • Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10.
  • Duhen T, Duhen R, Montler R, et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat Commun. 2018 2018 91;9:1–13.
  • Poschke IC, Hassel JC, Rodriguez-Ehrenfried A, et al. The outcome of ex vivo til expansion is highly influenced by spatial heterogeneity of the tumor t-cell repertoire and differences in intrinsic in vitro growth capacity between t-cell clones. Clin Cancer Res. 2020;26:4289–4301.
  • Tran E, Robbins PF, Rosenberg SA. ‘Final common pathway‘ of human cancer immunotherapy: targeting random somatic mutations. Nat Immunol. 2017;18(3):255–262.
  • Leone P, Shin EC, Perosa F, et al. MHC class i antigen processing and presenting machinery: Organization, function, and defects in tumor cells. J Natl Cancer Inst. 2013;105:1172–1187.
  • Chen HL, Gabrilovich D, Tampé R, et al. A functionally defective allele of TAP1 results in loss of MHC class I antigen presentation in a human lung cancer. Nat Genet. 1996;13:210–213.
  • Kloor M, Becker C, Benner A, et al. Immunoselective pressure and human leukocyte antigen class I antigen machinery defects in microsatellite unstable colorectal cancers. Cancer Res. 2005;65:6418–6424.
  • Restifo NP, Marincola FM, Kawakami Y, et al. Loss of functional beta2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. J Natl Cancer Inst. 1996;88:100–108.
  • Hicklin DJ, Wang Z, Arienti F, et al. β2-Microglobulin mutations, HLA class I antigen loss, and tumor progression in melanoma. J Clin Invest. 1998;101:2720–2729.
  • Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–421.
  • Efremova M, Finotello F, Rieder D, et al. Neoantigens generated by individual mutations and their role in cancer immunity and immunotherapy. Front Immunol. 2017;8. DOI: https://doi.org/10.3389/fimmu.2017.00008
  • Lauss M, Donia M, Harbst K, et al. Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma. Nat Commun. 2017;8:1–11.
  • Kristensen NP, Heeke C, Tvingsholm SA, et al. Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma. J Clin Invest. 2022;132.
  • Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–322.
  • Kumar V, Patel S, Tcyganov E, et al. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 2016;37:208–220.
  • Becker JC, Andersen MH, Schrama D, et al. Immune-suppressive properties of the tumor microenvironment. Cancer Immunol Immunother. 2013;62:1137–1148.
  • Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12(4):253–268.
  • Zhu S, Luo Z, Li X, et al. Tumor-associated macrophages: Role in tumorigenesis and immunotherapy implications. J Cancer. 2021;12:54–64.
  • Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: can Treg cells be a new therapeutic target? Cancer Science. 2019;110(7):2080–2089.
  • Morad G, Helmink BA, Sharma P, et al. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. 2021;184(21):5309–5337.
  • Meyer C, Cagnon L, Costa-Nunes CM, et al. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol Immunother. 2014;63(3):247–257.
  • Kodumudi KN, Weber A, Sarnaik AA, et al. Blockade of myeloid-derived suppressor cells after induction of lymphopenia improves adoptive t cell therapy in a murine model of melanoma. J Immunol. 2012;189:5147–5154.
  • Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol. 1999;163:5211–5218.
  • Tirosh I, Izar B, Prakadan SM, et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science. 2016;352:189–196.
  • Li H, van der Leun AM, Yofe I, et al. Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma. Cell. 2019;176:775–789.e18.
  • Baitsch L, Baumgaertner P, Devêvre E, et al. Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients. J Clin Invest. 2011;121:2350–2360.
  • Wherry EJ, Blattman JN, Murali-Krishna K, et al. Viral persistence alters cd8 t-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol. 2003;77:4911–4927.
  • van der Leun AM, Thommen DS, Schumacher TN. CD8+ T cell states in human cancer: insights from single-cell analysis. Nat Rev Cancer. 2020;20:218–232.
  • Blank CU, Haining WN, Held W, et al. Defining ‘T cell exhaustion.’ Nat Rev Immunol. 2019;19(11):665–674.
  • Morotti M, Albukhari A, Alsaadi A, et al. Promises and challenges of adoptive T-cell therapies for solid tumours. Br J Cancer. 2021;124:1759–1776.
  • Krishna S, Lowery FJ, Copeland AR, et al. Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer. Science. 2020;370:1328–1334. cited 2022 Jan 2.
  • Yang JC. Localization of indium-labeled tumor infiltrating lymphocytes.
  • Bernhard H, Neudorfer J, Gebhard K, et al. Adoptive transfer of autologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER2-overexpressing breast cancer. Cancer Immunol Immunother. 2008;57:271–280.
  • Kuczek DE, Larsen AMH, Thorseth ML, et al. Collagen density regulates the activity of tumor-infiltrating T cells. J Immunother Cancer. 2019;7:1–15.
  • Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011–1027.
  • Nagy JA, Chang SH, Dvorak AM, et al. Why are tumour blood vessels abnormal and why is it important to know? Br J Cancer. 2009;100:865–869.
  • Slaney CY, Kershaw MH, Darcy PK. Trafficking of T cells into tumors. Cancer Res. 2014;74:7168–7174.
  • Peng D, Kryczek I, Nagarsheth N, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature. 2015;527:249–253.
  • Anderson KG, Stromnes IM, Greenberg PD. Obstacles posed by the tumor microenvironment to t cell activity: a case for synergistic therapies. Cancer Cell. 2017;31:311–325.
  • O’Donnell JS, Teng MWL, Smyth MJ. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat Rev Clin Oncol. 2018;16(3):151–167. 2018.
  • Liu D, Jenkins RW, Sullivan RJ. Mechanisms of resistance to immune checkpoint blockade. Am J Clin Dermatol. 2019;20:41–54.
  • Schoenfeld AJ, Hellmann MD. Acquired resistance to immune checkpoint inhibitors. Cancer Cell. 2020;37:443–455.
  • Donia M, Harbst K, Van Buuren M, et al. Acquired immune resistance follows complete tumor regression without loss of target antigens or ifnγ signaling. Cancer Res. 2017;77:4562–4566.
  • Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to pd-1 blockade in melanoma. N Engl J Med. 2016;375:819–829.
  • Khong HT, Wang QJ, Rosenberg SA. Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: tumor escape by antigen loss and loss of MHC expression. J Immunother. 2004;27:184–190.
  • Verdegaal EME, De miranda NFCC, Visser M, et al. Neoantigen landscape dynamics during human melanoma-T cell interactions. Nature. 2016;536:91–95.
  • Kaluza KM, Thompson JM, Kottke TJ, et al. Adoptive T cell therapy promotes the emergence of genomically altered tumor escape variants. Int J Cancer. 2012;131:844–854.
  • Wylie B, Chee J, Forbes CA, et al. Acquired resistance during adoptive cell therapy by transcriptional silencing of immunogenic antigens. Oncoimmunology. 2019;8.
  • Vo DD, Prins RM, Begley JL, et al. Enhanced anti-tumor activity induced by adoptive T cell transfer and the adjunctive use of the HDAC Inhibitor LAQ824. Cancer Res. 2009;69:8693.
  • Koyama S, Akbay EA, Li YY, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016 71 2016;7:1–9.
  • Perez C, Jukica A, Listopad JJ, et al. Permissive expansion and homing of adoptively transferred T cells in tumor-bearing hosts. Int J Cancer. 2015;137:359–371.
  • Miao Y, Yang H, Levorse J, et al. Adaptive IMMUNE resistance emerges from tumor-initiating stem cells. Cell. 2019;177:1172.
  • Mehta A, Kim YJ, Robert L, et al. Immunotherapy resistance by inflammation-induced dedifferentiation. Cancer Discov. 2018;8:935–943.
  • Landsberg J, Kohlmeyer J, Renn M, et al. Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature. 2012;490:412–416.
  • Rohaan MW, Wilgenhof S, Jbag H. Adoptive cellular therapies: the current landscape. Virchows Arch. 2019;474:449–461.
  • Dafni U, Michielin O, Lluesma SM, et al. Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis. Ann Oncol. 2019;30:1902–1913.
  • Rosenberg SA. IL-2: the First Effective Immunotherapy for Human Cancer. J Immunol. 2014;192:5451–5458.
  • Scharping NE, V MA, Moreci RS, et al. The Tumor microenvironment represses t cell mitochondrial biogenesis to drive intratumoral t cell metabolic insufficiency and dysfunction. Immunity. 2016;45:374–388.
  • Almeida L, Lochner M, Berod L, et al. Metabolic pathways in T cell activation and lineage differentiation. Semin Immunol. 2016;28:514–524.
  • Biswas SK. Metabolic reprogramming of immune cells in cancer progression. Immunity. 2015;43:435–449.
  • Leone RD, Powell JD. Metabolism of immune cells in cancer. Nat Rev Cancer. 2020;20:516–531.
  • Kishton RJ, Sukumar M, Restifo NP. Metabolic regulation of t cell longevity and function in tumor immunotherapy. Cell Metab. 2017;26:94–109.
  • Pellegrino M, Del Bufalo F, De Angelis B, et al. Manipulating the metabolism to improve the efficacy of CAR T-cell immunotherapy. Cells. 2021;10:1–16.
  • Jenkins Y, Zabkiewicz J, Ottmann O, et al. Tinkering under the hood: Metabolic optimisation of car-t cell therapy. Antibodies. 2021;10:1–12.
  • Zhang M, Jin X, Sun R, et al. Optimization of metabolism to improve efficacy during CAR-T cell manufacturing. J Transl Med. 2021;19(1):1–11. 2021;19.
  • Buck MD, O’Sullivan D, Pearce EL. T cell metabolism drives immunity. J Exp Med. 2015;212:1345–1360.
  • O’Sullivan D, Pearce EL. Targeting T cell metabolism for therapy. Trends Immunol. 2015;36:71–80.
  • Maciver NJ, Michalek RD, Rathmell JC. Metabolic regulation of T lymphocytes. Annu Rev Immunol. 2013;31:259–283.
  • Chang CH, Pearce EL. Emerging concepts of T cell metabolism as a target of immunotherapy. Nat Immunol. 2016;17:364–368.
  • Rangel Rivera GO, Knochelmann HM, Dwyer CJ, et al. Fundamentals of T cell metabolism and strategies to enhance cancer Immunotherapy. Front Immunol. 2021;12:1–17.
  • Sukumar M, Liu J, Ji Y, et al. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J Clin Invest. 2013;123:4479–4488.
  • O’Sullivan D, vanderWindt GWJ, Huang SCC, et al. Memory CD8+ T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity. 2014;41:75–88.
  • van der Windt GJW, Everts B, Chang CH, et al. Mitochondrial respiratory capacity is a critical regulator of cd8 + t cell memory development. Immunity. 2012;36:68–78.
  • Hinrichs CS, Borman ZA, Cassard L, et al. Adoptively transferred effector cells derived from naïve rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc Natl Acad Sci U S A. 2009;106:17469–17474.
  • Chang CH, Qiu J, O’Sullivan D, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015;162:1229–1241.
  • Cascone T, McKenzie JA, Mbofung RM, et al. Increased tumor glycolysis characterizes immune resistance to adoptive t cell therapy. Cell Metab. 2018;27:977–987.e4.
  • DePeaux K, Delgoffe GM. Metabolic barriers to cancer immunotherapy. Nat Rev Immunol. 2021; 0123456789. Available from. DOI: https://doi.org/10.1038/s41577-021-00541-y
  • Wang Q, Holst J. L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia. Am J Cancer Res. 2015;5:1281–1294.
  • V SL, Rolf J, Emslie E, et al. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol. 2013;14:500–508.
  • Beckermann KE, Dudzinski SO, Rathmell JC. Dysfunctional T cell metabolism in the tumor microenvironment. Cytokine Growth Factor Rev. 2017;35:7–14.
  • Scharping NE, Rivadeneira DB, V MA, et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat Immunol. 2021;22:205–215.
  • Vardhana SA, Hwee MA, Berisa M, et al. Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. Nat Immunol. 2020;21:1022–1033.
  • Waickman AT, Powell JD. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol Rev. 2012;249:43–58.
  • Kishton RJ, Barnes CE, Nichols AG, et al. AMPK is essential to balance glycolysis and mitochondrial metabolism to control t-all cell stress and survival. Cell Metab. 2016;23:649–662.
  • Frauwirth KA, Riley JL, Harris MH, et al. The CD28 signaling pathway regulates glucose metabolism. Immunity. 2002;16:769–777.
  • V PR, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25:9543–9553.
  • Patsoukis N, Bardhan K, Chatterjee P, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015;6.
  • Ando M, Ito M, Srirat T, et al. Memory T cell, exhaustion, and tumor immunity. Immunol Med. 2020;43:1–9.
  • Angelin A, Gil-de-gómez L, Dahiya S, et al. Foxp3 reprograms t cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 2017;25:1282–1293.e7.
  • Geiger R, Rieckmann JC, Wolf T, et al. L-arginine modulates t cell metabolism and enhances survival and anti-tumor activity. Cell. 2016;167:829–842.e13.
  • Liu Y, Liang X, Dong W, et al. Tumor-repopulating cells induce pd-1 expression in cd8+ t cells by transferring kynurenine and ahr activation. Cancer Cell. 2018;33:480–494.e7.
  • Meireson A, Devos M, Brochez L. IDO expression in cancer: different compartment, different functionality? Front Immunol. 2020;11:1–17.
  • Brandacher G, Perathoner A, Ladurner R, et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res. 2006;12:1144–1151.
  • Mbongue JC, Nicholas DA, Torrez TW, et al. The role of indoleamine 2, 3-dioxygenase in immune suppression and autoimmunity. Vaccines (Basel). 2015;3:703–729.
  • Wang L, Fan J, Thompson LF, et al. CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J Clin Invest. 2011;121:2371–2382.
  • Allard B, Longhi MS, Robson SC, et al. The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev. 2017;276:121–144.
  • Sukumar M, Kishton RJ, Restifo NP. Metabolic reprograming of anti-tumor immunity. Curr Opin Immunol. 2017;46:14–22.
  • Duhen T, Duhen R, Montler R, et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat Commun. 2018; 9.
  • Gros A, Robbins PF, Yao X, et al. PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors. J Clin Invest. 2014;124:2246–2259.
  • Cohen CJ, Gartner JJ, Horovitz-Fried M, et al. Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes. J Clin Invest. 2015;125:3981–3991.
  • Kelderman S, Heemskerk B, Fanchi L, et al. Antigen-specific TIL therapy for melanoma: a flexible platform for personalized cancer immunotherapy. Eur J Immunol. 2016;46:1351–1360.
  • Arnaud M, Chiffelle J, Genolet R, et al. Sensitive identification of neoantigens and cognate TCRs in human solid tumors. Nat Biotechnol. 2021. DOI:https://doi.org/10.1038/s41587-021-01072-6.
  • Bianchi V, Harari A, Coukos G. Neoantigen-specific adoptive cell therapies for cancer: Making t-cell products more personal. Front Immunol. 2020;11:1–11.
  • Krishna S, Lowery FJ, Copeland AR, et al. Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer. Science. 2020;370:1328–1334.
  • Klebanoff CA, Finkelstein SE, Surman DR, et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8 + T Cells. Proc Natl Acad Sci U S A. 2004;101:1969–1974.
  • Hinrichs CS, Spolski R, Paulos CM, et al. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood. 2008;111:5326–5333.
  • Klein Geltink RI, Edwards-Hicks J, Apostolova P, et al. Metabolic conditioning of CD8+ effector T cells for adoptive cell therapy. Nat Metab. 2020;2:703–716.
  • Crompton JG, Sukumar M, Roychoudhuri R, et al. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res. 2015;75:296–305.
  • Dwyer CJ, Knochelmann HM, Smith AS, et al. Fueling cancer immunothery with common gamma chain cytokines. Front Immunol. 2019;10:1–18.
  • Parisi G, Saco JD, Salazar FB, et al. Persistence of adoptively transferred T cells with a kinetically engineered IL-2 receptor agonist. Nat Commun. 2020;11:1–12.
  • Lynn RC, Weber EW, Sotillo E, et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature. 2019;576:293–300.
  • Saini KS, Svane IM, Juan M, et al. Manufacture of adoptive cell therapies at academic cancer centers: scientific, safety and regulatory challenges. Ann Oncol. 2022;33:6–12.
  • Goff SL, Rosenberg SA. BRAF inhibition: bridge or boost to t-cell therapy? Clin Cancer Res. 2019;25:2682–2684. cited 2022 Jan 5

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