Naturally occurring T cell mutations enhance engineered T cell therapies

Nature. 2024 Feb;626(7999):626-634. doi: 10.1038/s41586-024-07018-7. Epub 2024 Feb 7.


Adoptive T cell therapies have produced exceptional responses in a subset of patients with cancer. However, therapeutic efficacy can be hindered by poor T cell persistence and function1. In human T cell cancers, evolution of the disease positively selects for mutations that improve fitness of T cells in challenging situations analogous to those faced by therapeutic T cells. Therefore, we reasoned that these mutations could be co-opted to improve T cell therapies. Here we systematically screened the effects of 71 mutations from T cell neoplasms on T cell signalling, cytokine production and in vivo persistence in tumours. We identify a gene fusion, CARD11-PIK3R3, found in a CD4+ cutaneous T cell lymphoma2, that augments CARD11-BCL10-MALT1 complex signalling and anti-tumour efficacy of therapeutic T cells in several immunotherapy-refractory models in an antigen-dependent manner. Underscoring its potential to be deployed safely, CARD11-PIK3R3-expressing cells were followed up to 418 days after T cell transfer in vivo without evidence of malignant transformation. Collectively, our results indicate that exploiting naturally occurring mutations represents a promising approach to explore the extremes of T cell biology and discover how solutions derived from evolution of malignant T cells can improve a broad range of T cell therapies.

MeSH terms

  • CARD Signaling Adaptor Proteins / genetics
  • CARD Signaling Adaptor Proteins / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Cytokines / metabolism
  • Evolution, Molecular*
  • Guanylate Cyclase / genetics
  • Guanylate Cyclase / metabolism
  • Humans
  • Immunotherapy, Adoptive* / methods
  • Lymphoma, T-Cell, Cutaneous* / genetics
  • Lymphoma, T-Cell, Cutaneous* / immunology
  • Lymphoma, T-Cell, Cutaneous* / pathology
  • Lymphoma, T-Cell, Cutaneous* / therapy
  • Mutation*
  • Phosphatidylinositol 3-Kinases
  • Signal Transduction / genetics
  • T-Lymphocytes* / immunology
  • T-Lymphocytes* / metabolism
  • T-Lymphocytes* / transplantation


  • BCL10 protein, human
  • CARD Signaling Adaptor Proteins
  • CARD11 protein, human
  • Cytokines
  • Guanylate Cyclase
  • MALT1 protein, human
  • Phosphatidylinositol 3-Kinases
  • PIK3R3 protein, human