T cell receptor binding affinity governs the functional profile of cancer-specific CD8+ T cells

Abstract

Summary Antigen-specific T cell receptor (TCR) gene transfer via patient-derived T cells is an attractive approach to cancer therapy, with the potential to circumvent immune regulatory networks. However, high-affinity tumour-specific TCR clonotypes are typically deleted from the available repertoire during thymic selection because the vast majority of targeted epitopes are derived from autologous proteins. This process places intrinsic constraints on the efficacy of T cell-based cancer vaccines and therapeutic strategies that employ naturally generated tumour-specific TCRs. In this study, we used altered peptide ligands and lentivirus-mediated transduction of affinity-enhanced TCRs selected by phage display to study the functional properties of CD8+ T cells specific for three different tumour-associated peptide antigens across a range of binding parameters. The key findings were: (i) TCR affinity controls T cell antigen sensitivity and polyfunctionality; (ii) supraphysiological affinity thresholds exist, above which T cell function cannot be improved; and (iii) T cells transduced with very high-affinity TCRs exhibit cross-reactivity with self-derived peptides presented by the restricting human leucocyte antigen. Optimal system-defined affinity windows above the range established for natural tumour-specific TCRs therefore allow the enhancement of T cell effector function without off-target effects. These findings have major implications for the rational design of novel TCR-based biologics underpinned by rigorous preclinical evaluation.

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References 81

1. 1.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

2. 2.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

3. 3.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

4. 4.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

5. 5.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

6. 6.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

7. 7.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

8. 8.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

9. 9.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

10. 10.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

11. 11.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

12. 12.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

13. 13.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

14. 14.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

15. 15.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

16. 16.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

17. 17.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

18. 18.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

19. 19.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

20. 20.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

21. 21.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

22. 22.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

23. 23.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

24. 24.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

25. 25.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

26. 26.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

27. 27.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

28. 28.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

29. 29.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

30. 30.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

31. 31.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

32. 32.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

33. 33.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

34. 34.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

35. 35.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

36. 36.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

37. 37.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

38. 38.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

39. 39.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

40. 40.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

41. 41.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

42. 42.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

43. 43.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

44. 44.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

45. 45.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

46. 46.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

47. 47.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

48. 48.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

49. 49.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

50. 50.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

51. 51.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

52. 52.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

53. 53.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

54. 54.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

55. 55.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

56. 56.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

57. 57.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

58. 58.
    Protein kinase inhibitors substantially improve the physical detection of T-cells with peptide-MHC tetramers · 2009

    No notice
59. 59.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

60. 60.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

61. 61.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

62. 62.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

63. 63.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

64. 64.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

65. 65.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

66. 66.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

67. 67.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

68. 68.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

69. 69.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

70. 70.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

71. 71.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

72. 72.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

73. 73.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

74. 74.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

75. 75.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

76. 76.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

77. 77.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

78. 78.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

79. 79.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

80. 80.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

81. 81.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

Cited by papers we hold 4

• Rapid Identification of the Tumor-Specific Reactive TIL Repertoire via Combined Detection of CD137, TNF, and IFNγ, Following Recognition of Autologous Tumor-Antigens · 2021
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• High Peptide Dose Vaccination Promotes the Early Selection of Tumor Antigen-Specific CD8 T-Cells of Enhanced Functional Competence · 2020
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• Molecular Rules Underpinning Enhanced Affinity Binding of Human T Cell Receptors Engineered for Immunotherapy · 2020
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• New development in CAR-T cell therapy · 2017
  No notice

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