Reprogramming T Cell Differentiation and Exhaustion in CAR-T Cell Therapy

Overview

Journal J Hematol Oncol

Publisher Biomed Central

Specialties Hematology
Oncology

Date 2023 Oct 26

PMID 37880715

Authors

Yannick Bulliard

Borje S Andersson

Mehmet A Baysal

Jason Damiano

Apostolia M Tsimberidou

Affiliations

Soon will be listed here.

Abstract

T cell differentiation is a highly regulated, multi-step process necessary for the progressive establishment of effector functions, immunological memory, and long-term control of pathogens. In response to strong stimulation, as seen in severe or chronic infections or cancer, T cells acquire a state of hypo-responsiveness known as exhaustion, limiting their effector function. Recent advances in autologous chimeric antigen receptor (CAR)-T cell therapies have revolutionized the treatment of hematologic malignancies by taking advantage of the basic principles of T cell biology to engineer products that promote long-lasting T cell response. However, many patients' malignancies remain unresponsive to treatment or are prone to recur. Discoveries in T cell biology, including the identification of key regulators of differentiation and exhaustion, offer novel opportunities to have a durable impact on the fate of CAR-T cells after infusion. Such next-generation CAR-T cell therapies and their clinical implementation may result in the next leap forward in cancer treatment for selected patients. In this context, this review summarizes the foundational principles of T cell differentiation and exhaustion and describes how they can be utilized and targeted to further improve the design and efficacy of CAR-T cell therapies.

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References

Simonetta F, Lohmeyer J, Hirai T, Maas-Bauer K, Alvarez M, Wenokur A . Allogeneic CAR Invariant Natural Killer T Cells Exert Potent Antitumor Effects through Host CD8 T-Cell Cross-Priming. Clin Cancer Res. 2021; 27(21):6054-6064. PMC: 8563377. DOI: 10.1158/1078-0432.CCR-21-1329. View

Bengsch B, Ohtani T, Khan O, Setty M, Manne S, OBrien S . Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells. Immunity. 2018; 48(5):1029-1045.e5. PMC: 6010198. DOI: 10.1016/j.immuni.2018.04.026. View

Brummelman J, Mazza E, Alvisi G, Colombo F, Grilli A, Mikulak J . High-dimensional single cell analysis identifies stem-like cytotoxic CD8 T cells infiltrating human tumors. J Exp Med. 2018; 215(10):2520-2535. PMC: 6170179. DOI: 10.1084/jem.20180684. View

Maude S, Laetsch T, Buechner J, Rives S, Boyer M, Bittencourt H . Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018; 378(5):439-448. PMC: 5996391. DOI: 10.1056/NEJMoa1709866. View

Deng Q, Han G, Puebla-Osorio N, Ma M, Strati P, Chasen B . Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. Nat Med. 2020; 26(12):1878-1887. PMC: 8446909. DOI: 10.1038/s41591-020-1061-7. View

Zhang M, Jin X, Sun R, Xiong X, Wang J, Xie D . Optimization of metabolism to improve efficacy during CAR-T cell manufacturing. J Transl Med. 2021; 19(1):499. PMC: 8650271. DOI: 10.1186/s12967-021-03165-x. View

Scott A, Dundar F, Zumbo P, Chandran S, Klebanoff C, Shakiba M . TOX is a critical regulator of tumour-specific T cell differentiation. Nature. 2019; 571(7764):270-274. PMC: 7698992. DOI: 10.1038/s41586-019-1324-y. View

Chen J, Lopez-Moyado I, Seo H, Lio C, Hempleman L, Sekiya T . NR4A transcription factors limit CAR T cell function in solid tumours. Nature. 2019; 567(7749):530-534. PMC: 6546093. DOI: 10.1038/s41586-019-0985-x. View

Behr F, Kragten N, Wesselink T, Nota B, van Lier R, Amsen D . Blimp-1 Rather Than Hobit Drives the Formation of Tissue-Resident Memory CD8 T Cells in the Lungs. Front Immunol. 2019; 10:400. PMC: 6416215. DOI: 10.3389/fimmu.2019.00400. View

10.

Kim M, Ouyang W, Liao W, Zhang M, Li M . The transcription factor Foxo1 controls central-memory CD8+ T cell responses to infection. Immunity. 2013; 39(2):286-97. PMC: 3809840. DOI: 10.1016/j.immuni.2013.07.013. View

11.

Shin H, Blackburn S, Intlekofer A, Kao C, Angelosanto J, Reiner S . A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Immunity. 2009; 31(2):309-20. PMC: 2747257. DOI: 10.1016/j.immuni.2009.06.019. View

12.

Kallies A, Zehn D, Utzschneider D . Precursor exhausted T cells: key to successful immunotherapy?. Nat Rev Immunol. 2019; 20(2):128-136. DOI: 10.1038/s41577-019-0223-7. View

13.

Seo H, Chen J, Gonzalez-Avalos E, Samaniego-Castruita D, Das A, Wang Y . TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8 T cell exhaustion. Proc Natl Acad Sci U S A. 2019; 116(25):12410-12415. PMC: 6589758. DOI: 10.1073/pnas.1905675116. View

14.

Guo Y, Feng K, Liu Y, Wu Z, Dai H, Yang Q . Phase I Study of Chimeric Antigen Receptor-Modified T Cells in Patients with EGFR-Positive Advanced Biliary Tract Cancers. Clin Cancer Res. 2017; 24(6):1277-1286. DOI: 10.1158/1078-0432.CCR-17-0432. View

15.

Jaccard A, Wyss T, Maldonado-Perez N, Rath J, Bevilacqua A, Peng J . Reductive carboxylation epigenetically instructs T cell differentiation. Nature. 2023; 621(7980):849-856. DOI: 10.1038/s41586-023-06546-y. View

16.

Yang Y, Jacoby E, Fry T . Challenges and opportunities of allogeneic donor-derived CAR T cells. Curr Opin Hematol. 2015; 22(6):509-515. PMC: 4636084. DOI: 10.1097/MOH.0000000000000181. View

17.

Ghoneim H, Fan Y, Moustaki A, Abdelsamed H, Dash P, Dogra P . De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation. Cell. 2017; 170(1):142-157.e19. PMC: 5568784. DOI: 10.1016/j.cell.2017.06.007. View

18.

Wagle M, Vervoort S, Kelly M, Van Der Byl W, Peters T, Martin B . Antigen-driven EGR2 expression is required for exhausted CD8 T cell stability and maintenance. Nat Commun. 2021; 12(1):2782. PMC: 8119420. DOI: 10.1038/s41467-021-23044-9. View

19.

Mognol G, Spreafico R, Wong V, Scott-Browne J, Togher S, Hoffmann A . Exhaustion-associated regulatory regions in CD8 tumor-infiltrating T cells. Proc Natl Acad Sci U S A. 2017; 114(13):E2776-E2785. PMC: 5380094. DOI: 10.1073/pnas.1620498114. View

20.

Sade-Feldman M, Yizhak K, Bjorgaard S, Ray J, de Boer C, Jenkins R . Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell. 2018; 175(4):998-1013.e20. PMC: 6641984. DOI: 10.1016/j.cell.2018.10.038. View