Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

IMMUNOTHERAPY

Who wins the combat, CAR or TCR?

Leukemia volume 37, pages 1953–1962 (2023)Cite this article

Subjects

Abstract

Chimeric antigen receptor T (CAR-T) cell therapy has drawn increasing attention over the last few decades given its remarkable effectiveness and breakthroughs in treating B cell hematological malignancies. Even though CAR-T cell therapy has outstanding clinical successes, most treated patients still relapse after infusion. CARs are derived from the T cell receptor (TCR) complex and co-stimulatory molecules associated with T cell activation; however, the similarities and differences between CARs and endogenous TCRs regarding their sensitivity, signaling pathway, killing mechanisms, and performance are still not fully understood. In this review, we discuss the parallel comparisons between CARs and TCRs from various aspects and how these current findings might provide novel insights and contribute to improvement of CAR-T cell therapy efficacy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Structure of chimeric antigen receptors (CARs).
Fig. 2: Structure of TCR complex and CAR.
Fig. 3: Structure of classical and non-classical immune synapse (IS).
Fig. 4: Mechanisms of transition from mechanical forces into biochemical reactions in T cells.
Fig. 5: Kinetics of T cell activation signaling and cytotoxicity.

Similar content being viewed by others

References

  1. Sakemura R, Cox MJ, Hefazi M, Siegler EL, Kenderian SS. Resistance to cart cell therapy: Lessons learned from the treatment of hematological malignancies. Leuk lymphoma. 2021;62:2052–63.

    Article  CAS  PubMed  Google Scholar 

  2. June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. Car T cell immunotherapy for human cancer. Science. 2018;359:1361–5.

    Article  CAS  PubMed  Google Scholar 

  3. Benmebarek M-R, Karches C, Cadilha B, Lesch S, Endres S, Kobold S. Killing mechanisms of chimeric antigen receptor (CAR) T cells. Int J Mol Sci. 2019;20:1283.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Center for Drug Evaluation and Research. FDA D.I.S.C.O. burst: Approval of ABECMA (idacabtagene vicleucel) [Internet]. U.S. Food and Drug Administration. FDA; 2021 [cited 2021Oct31]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-abecma-idecabtagene-vicleucel-first-fda-approved-cell-based

  5. Baulu E, Gardet C, Chuvin N, Depil S. TCR-engineered T cell therapy in solid tumors: State of the art and Perspectives. Sci Adv. 2023;9:eadf3700.

  6. Sadelain M, Brentjens R, Rivière I. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013;3:388–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Faroudi M, Utzny C, Salio M, Cerundolo V, Guiraud M, Müller S, et al. Lytic versus stimulatory synapse in cytotoxic T lymphocyte/target cell interaction: Manifestation of a dual activation threshold. Proc Natl Acad Sci. 2003;100:14145–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sykulev Y, Joo M, Vturina I, Tsomides TJ, Eisen HN. Evidence that a single peptide–MHC complex on a target cell can elicit a cytolytic T cell response. Immunity. 1996;4:565–71.

    Article  CAS  PubMed  Google Scholar 

  9. Jensen MC, Riddell SR. Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells. Immunol Rev. 2013;257:127–44.

    Article  Google Scholar 

  10. Purbhoo MA, Irvine DJ, Huppa JB, Davis MM. T cell killing does not require the formation of a stable mature immunological synapse. Nat Immunol. 2004;5:524–30.

    Article  CAS  PubMed  Google Scholar 

  11. Valitutti S, Müller S, Dessing M, Lanzavecchia A. Different responses are elicited in cytotoxic T lymphocytes by different levels of T cell receptor occupancy. J Exp Med. 1996;183:1917–21.

    Article  CAS  PubMed  Google Scholar 

  12. Porgador A, Yewdell JW, Deng Y, Bennink JR, Germain RN. Localization, quantitation, and in situ detection of specific peptide–MHC class I complexes using a monoclonal antibody. Immunity. 1997;6:715–26.

    Article  CAS  PubMed  Google Scholar 

  13. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene CILOLEUCEL car T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Watanabe K, Terakura S, Martens AC, van Meerten T, Uchiyama S, Imai M, et al. Target antigen density governs the efficacy of anti–CD20-CD28-CD3 ζ chimeric antigen receptor–modified effector CD8+ T cells. J Immunol. 2015;194:911–20.

    Article  CAS  PubMed  Google Scholar 

  15. Hudecek M, Lupo-Stanghellini M-T, Kosasih PL, Sommermeyer D, Jensen MC, Rader C, et al. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. Clin Cancer Res. 2013;19:3153–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Walker AJ, Majzner RG, Zhang L, Wanhainen K, Long AH, Nguyen SM, et al. Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Mol Ther. 2017;25:2189–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lindner SE, Johnson SM, Brown CE, Wang LD. Chimeric antigen receptor signaling: Functional consequences and design implications. Sci Adv. 2020;6:eaaz3223.

  18. Foote J, Eisen HN. Breaking the affinity ceiling for antibodies and T cell receptors. Proc Natl Acad Sci. 2000;97:10679–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Harris DT, Hager MV, Smith SN, Cai Q, Stone JD, Kruger P, et al. Comparison of T cell activities mediated by human tcrs and cars that use the same recognition domains. J Immunol. 2018;200:1088–100.

    Article  CAS  PubMed  Google Scholar 

  20. Stone JD, Harris DT, Soto CM, Chervin AS, Aggen DH, Roy EJ, et al. A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control. Cancer Immunol, Immunother. 2014;63:1163–76.

    Article  CAS  PubMed  Google Scholar 

  21. Oren R, Hod-Marco M, Haus-Cohen M, Thomas S, Blat D, Duvshani N, et al. Functional comparison of engineered T cells carrying a native TCR versus TCR-like antibody–based chimeric antigen receptors indicates affinity/avidity thresholds. J Immunol. 2014;193:5733–43.

    Article  CAS  PubMed  Google Scholar 

  22. Isakov N. Immunoreceptor tyrosine-based activation motif (ITAM), a unique module linking antigen and Fc receptors to their signaling cascades. J Leukoc Biol. 1997;61:6–16.

    Article  CAS  PubMed  Google Scholar 

  23. Love PE, Hayes SM. ITAM-mediated signaling by the T-cell antigen receptor. Cold Spring Harb Perspect Biol. 2010;2:a002485.

  24. Underhill DM, Goodridge HS. The Many Faces of Itams. Trends Immunol. 2007;28:66–73.

    Article  CAS  PubMed  Google Scholar 

  25. GEISLER C, LARSEN JK, PLESNER T. Identification of alphabeta and gammadelta T cell receptor-positive cells. Scand J Immunol. 1988;28:741–5.

    Article  CAS  PubMed  Google Scholar 

  26. James JR. Tuning itam multiplicity on T cell receptors can control potency and selectivity to ligand density. Sci Signal. 2018;11:eaan1088.

  27. Hwang J-R, Byeon Y, Kim D, Park S-G. Recent insights of T cell receptor-mediated signaling pathways for T cell activation and development. Exp Mol Med. 2020;52:750–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hedrick SM, Cohen DI, Nielsen EA, Davis MM. Isolation of cdna clones encoding T cell-specific membrane-associated proteins. Nature. 1984;308:149–53.

    Article  CAS  PubMed  Google Scholar 

  29. Malissen M, Minard K, Mjolsness S, Kronenberg M, Goverman J, Hunkapiller T, et al. Mouse T cell antigen receptor: Structure and organization of constant and joining gene segments encoding the β polypeptide. Cell. 1984;37:1101–10.

    Article  CAS  PubMed  Google Scholar 

  30. Borst J, Coligan JE, Oettgen H, Pessano S, Malin R, Terhorst C. The δ- and ε-chains of the human T3/T-cell receptor complex are distinct polypeptides. Nature. 1984;312:455–8.

    Article  CAS  PubMed  Google Scholar 

  31. Holst J, Wang H, Eder KD, Workman CJ, Boyd KL, Baquet Z, et al. Scalable signaling mediated by T cell antigen receptor–CD3 itams ensures effective negative selection and prevents autoimmunity. Nat Immunol. 2008;9:658–66.

    Article  CAS  PubMed  Google Scholar 

  32. Guy CS, Vignali KM, Temirov J, Bettini ML, Overacre AE, Smeltzer M, et al. Distinct TCR signaling pathways drive proliferation and cytokine production in T cells. Nat Immunol. 2013;14:262–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Salter AI, Rajan A, Kennedy JJ, Ivey RG, Shelby SA, Leung I, et al. Comparative analysis of TCR and car signaling informs car designs with superior antigen sensitivity and in vivo function. Sci Signal. 2021;14.

  34. Soares H, Lasserre R, Alcover A. Orchestrating cytoskeleton and intracellular vesicle traffic to build functional immunological synapses. Immunol Rev. 2013;256:118–32.

    Article  CAS  PubMed  Google Scholar 

  35. Alarcón B, Mestre D, Martínez-Martín N. The immunological synapse: A cause or consequence of T-cell receptor triggering? Immunology 2011;133:420–5.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Li R, Ma C, Cai H, Chen W. The car T‐Cell Mechanoimmunology at a glance. Advanced. Science. 2020;7:2002628.

    CAS  Google Scholar 

  37. Watanabe K, Kuramitsu S, Posey AD, June CH Expanding the therapeutic window for car T cell therapy in solid tumors: The knowns and unknowns of Car T cell biology. Front Immunol. 2018;9:2486.

  38. van der Merwe PA, Davis SJ, Shaw AS, Dustin ML. Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition. Semin Immunol. 2000;12:5–21.

    Article  Google Scholar 

  39. Xiong W, Chen Y, Kang X, Chen Z, Zheng P, Hsu Y-H, et al. Immunological Synapse predicts effectiveness of chimeric antigen receptor cells. Mol Ther. 2018;26:963–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Davenport AJ, Cross RS, Watson KA, Liao Y, Shi W, Prince HM, et al. Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity. Proc Natl Acad Sci. 2018;115:E2068–76.

  41. Saito T, Germain RN. Predictable acquisition of a new MHC recognition specificity following expression of a transfected T-cell receptor β-chain gene. Nature. 1987;329:256–9.

    Article  CAS  PubMed  Google Scholar 

  42. DembiĆ Z, Haas W, Weiss S, McCubrey J, Kiefer H, von Boehmer H, et al. Transfer of specificity by murine α and β T-cell receptor genes. Nature. 1986;320:232–8.

    Article  PubMed  Google Scholar 

  43. Samelson LE, Patel MD, Weissman AM, Harford JB, Klausner RD. Antigen activation of murine T cells induces tyrosine phosphorylation of a polypeptide associated with the T cell antigen receptor. Cell. 1986;46:1083–90.

    Article  CAS  PubMed  Google Scholar 

  44. Nolz JC, Gomez TS, Zhu P, Li S, Medeiros RB, Shimizu Y, et al. The wave2 complex regulates actin cytoskeletal reorganization and CRAC-mediated calcium entry during T cell activation. Curr Biol. 2006;16:24–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Le Floc’h A, Tanaka Y, Bantilan NS, Voisinne G, Altan-Bonnet G, Fukui Y, et al. Annular PIP3 accumulation controls actin architecture and modulates cytotoxicity at the immunological synapse. J Exp Med. 2013;210:2721–37.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Blumenthal D, Burkhardt JK. Multiple actin networks coordinate mechanotransduction at the immunological synapse. J. Cell Biol. 2020;219:e201911058.

  47. Yi J, Wu XS, Crites T, Hammer JA. Actin retrograde flow and Actomyosin II arc contraction drive receptor cluster dynamics at the immunological synapse in Jurkat T cells. Mol Biol Cell. 2012;23:834–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Stern LJ, Aivazian D. Nat Struct Biol. 2000;7:1023–6.

    Article  PubMed  Google Scholar 

  49. Lee MS, Glassman CR, Deshpande NR, Badgandi HB, Parrish HL, Uttamapinant C, et al. A mechanical switch couples T cell receptor triggering to the cytoplasmic juxtamembrane regions of CD3ζζ. Immunity. 2015;43:227–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Swamy M, Beck-Garcia K, Beck-Garcia E, Hartl FA, Morath A, Yousefi OS, et al. A cholesterol-based allostery model of T cell receptor phosphorylation. Immunity. 2016;44:1091–101.

    Article  CAS  PubMed  Google Scholar 

  51. Das DK, Feng Y, Mallis RJ, Li X, Keskin DB, Hussey RE, et al. Force-dependent transition in the T-cell receptor β-subunit allosterically regulates peptide discrimination and PMHC bond lifetime. Proc Natl Acad Sci. 2015;112:1517–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Xu C, Gagnon E, Call ME, Schnell JR, Schwieters CD, Carman CV, et al. Regulation of T cell receptor activation by dynamic membrane binding of the cd3ɛ cytoplasmic tyrosine-based motif. Cell. 2008;135:702–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Courtney AH, Lo W-L, Weiss A. TCR signaling: Mechanisms of initiation and propagation. Trends Biochemical Sci. 2018;43:108–23.

    Article  CAS  Google Scholar 

  54. Joseph N, Reicher B, Barda-Saad M. The calcium feedback loop and T cell activation: How Cytoskeleton Networks Control intracellular calcium flux. Biochimica et Biophysica Acta (BBA) - Biomembranes. 2014;1838:557–68.

    Article  CAS  PubMed  Google Scholar 

  55. Schmidt J, Dojcinovic D, Guillaume P, Luescher I. Analysis, isolation, and activation of antigen-specific CD4+ and CD8+ T cells by soluble MHC-peptide complexes. Front. Immunol. 2013;4:218.

  56. Gacerez AT, Arellano B, Sentman CL. How chimeric antigen receptor design affects adoptive T cell therapy. J Cell Physiol. 2016;231:2590–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bridgeman JS, Hawkins RE, Bagley S, Blaylock M, Holland M, Gilham DE. The optimal antigen response of chimeric antigen receptors harboring the CD3ζ transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. J Immunol. 2010;184:6938–49.

    Article  CAS  PubMed  Google Scholar 

  58. Chang ZNL, Lorenzini MH, Chen X, Tran U, Bangayan NJ, Chen YY. Rewiring T-cell responses to soluble factors with chimeric antigen receptors. Nat Chem Biol. 2018;14:317–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lindner SE, Johnson SM, Brown CE, Wang LD. Chimeric antigen receptor signaling: Functional consequences and design implications. Science Advances. 2020;6:eaaz3223.

  60. Salter AI, Ivey RG, Kennedy JJ, Voillet V, Rajan A, Alderman EJ, et al. Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function. Sci Signal. 2018;11:eaat6753.

  61. O’Leary MC, Lu X, Huang Y, Lin X, Mahmood I, Przepiorka D, et al. FDA approval summary: Tisagenlecleucel for treatment of patients with relapsed or refractory B-cell precursor Acute lymphoblastic leukemia. Clin Cancer Res. 2019;25:1142–6.

    Article  PubMed  Google Scholar 

  62. Meiraz A, Garber OG, Harari S, Hassin D, Berke G. Switch from perforin-expressing to perforin-deficient CD8+T cells accounts for two distinct types of effector cytotoxic T lymphocytesin vivo. Immunology. 2009;128:69–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Cullen SP, Martin SJ. Mechanisms of granule-dependent killing. Cell Death Differ. 2007;15:251–62.

    Article  PubMed  Google Scholar 

  64. Stinchcombe JC, Majorovits E, Bossi G, Fuller S, Griffiths GM. Centrosome polarization delivers secretory granules to the immunological synapse. Nature. 2006;443:462–5.

    Article  CAS  PubMed  Google Scholar 

  65. Hong LK, Chen Y, Smith CC, Montgomery SA, Vincent BG, Dotti G, et al. CD30-redirected chimeric antigen receptor T cells target CD30+ and CD30− embryonal carcinoma via antigen-dependent and FAS/FASL interactions. Cancer Immunol Res. 2018;6:1274–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Davenport AJ, Jenkins MR, Cross RS, Yong CS, Prince HM, Ritchie DS, et al. Car-T cells inflict sequential killing of multiple tumor target cells. Cancer Immunol Res. 2015;3:483–94.

    Article  CAS  PubMed  Google Scholar 

  67. Jenkins MR, Rudd-Schmidt JA, Lopez JA, Ramsbottom KM, Mannering SI, Andrews DM, et al. Failed CTL/Nk cell killing and cytokine hypersecretion are directly linked through prolonged synapse time. J Exp Med. 2015;212:307–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Benmebarek M-R, Karches C, Cadilha B, Lesch S, Endres S, Kobold S. Killing mechanisms of chimeric antigen receptor (CAR) T cells. Int J Mol Sci. 2019;20:1283.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Riviere I, Gallardo HF, Hagani AB, Sadelain M. Retroviral-mediated gene transfer in primary murine and human T-lymphocytes. Mol Biotechnol. 2000;15:133–42.

    Article  CAS  PubMed  Google Scholar 

  70. Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, et al. Targeting a car to the TRAC locus with CRISPR/cas9 enhances tumour rejection. Nature. 2017;543:113–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Stenger D, Stief TA, Kaeuferle T, Willier S, Rataj F, Schober K, et al. Endogenous TCR promotes in vivo persistence of CD19-car-T cells compared to a CRISPR/Cas9-mediated TCR knockout car. Blood. 2020;136:1407–18.

    Article  PubMed  Google Scholar 

  72. Wang Z, Li N, Feng K, Chen M, Zhang Y, Liu Y, et al. Phase I study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors. Cell Mol Immunol. 2021;18:2188–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wachsmann TL, Wouters AK, Remst DF, Hagedoorn RS, Meeuwsen MH, van Diest E, et al. Comparing car and TCR engineered T cell performance as a function of tumor cell exposure. OncoImmunology. 2022;11:2033528.

Download references

Acknowledgements

This work was supported in part through the National Cancer Institute (R37CA266344), Department of Defense (CA201127), the Mayo Clinic Center for Individualized Medicine, the Mayo Clinic Center for Regenerative Biotherapeutics, the Mayo Clinic Comprehensive Cancer Center, and the Henry J Predolin Foundation.

Author information

Authors and Affiliations

  1. T Cell Engineering, Mayo Clinic, Rochester, MN, USA

    Kun Yun, Elizabeth L. Siegler & Saad S. Kenderian

  2. Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA

    Kun Yun & Saad S. Kenderian

  3. Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA

    Kun Yun & Saad S. Kenderian

  4. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    Elizabeth L. Siegler & Saad S. Kenderian

  5. Department of Immunology, Mayo Clinic, Rochester, MN, USA

    Saad S. Kenderian

Authors
  1. Kun Yun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth L. Siegler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Saad S. Kenderian
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KY wrote the manuscript. ELS and SSK edited the manuscript. All authors edited and approved the final version of the manuscript.

Corresponding author

Correspondence to Saad S. Kenderian.

Ethics declarations

Competing interests

SSK is an inventor on patents in the field of CAR immunotherapy that are licensed to Novartis (through an agreement between Mayo Clinic, University of Pennsylvania, and Novartis), Humanigen (through Mayo Clinic), Mettaforge (through Mayo Clinic), Sendero (through Mayo Clinic), and MustangBio (through Mayo Clinic). SSK receives research funding from Kite, Gilead, Juno, Celgene, Novartis, Humanigen, MorphoSys, Tolero, Sunesis, LeahLabs, and Lentigen. SSK has participated in advisory meetings of Juno, Celgene, Kite, Gilead, LeahLabs, CapstanBio, Torque, Luminary, and Humanigen. SSK has participated in data safety monitoring boards of Humanigen. The other authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yun, K., Siegler, E.L. & Kenderian, S.S. Who wins the combat, CAR or TCR?. Leukemia 37, 1953–1962 (2023). https://doi.org/10.1038/s41375-023-01976-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-023-01976-z

Search

Advanced search

Quick links