Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy

Nature. 2019 Dec;576(7787):471-476. doi: 10.1038/s41586-019-1821-z. Epub 2019 Dec 11.

Abstract

Adoptive cell therapy represents a new paradigm in cancer immunotherapy, but it can be limited by the poor persistence and function of transferred T cells1. Here we use an in vivo pooled CRISPR-Cas9 mutagenesis screening approach to demonstrate that, by targeting REGNASE-1, CD8+ T cells are reprogrammed to long-lived effector cells with extensive accumulation, better persistence and robust effector function in tumours. REGNASE-1-deficient CD8+ T cells show markedly improved therapeutic efficacy against mouse models of melanoma and leukaemia. By using a secondary genome-scale CRISPR-Cas9 screening, we identify BATF as the key target of REGNASE-1 and as a rheostat that shapes antitumour responses. Loss of BATF suppresses the increased accumulation and mitochondrial fitness of REGNASE-1-deficient CD8+ T cells. By contrast, the targeting of additional signalling factors-including PTPN2 and SOCS1-improves the therapeutic efficacy of REGNASE-1-deficient CD8+ T cells. Our findings suggest that T cell persistence and effector function can be coordinated in tumour immunity and point to avenues for improving the efficacy of adoptive cell therapy for cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / deficiency
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • CRISPR-Cas Systems / genetics
  • Disease Models, Animal
  • Female
  • Gene Deletion
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Leukemia / genetics
  • Leukemia / immunology*
  • Leukemia / metabolism
  • Leukemia / therapy*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Melanoma / genetics
  • Melanoma / immunology*
  • Melanoma / metabolism
  • Melanoma / therapy*
  • Mice
  • Mitochondria / metabolism
  • Molecular Targeted Therapy*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / metabolism
  • Reproducibility of Results
  • Ribonucleases / deficiency
  • Ribonucleases / genetics
  • Ribonucleases / immunology
  • Ribonucleases / metabolism*
  • Suppressor of Cytokine Signaling 1 Protein / genetics
  • Suppressor of Cytokine Signaling 1 Protein / metabolism
  • Tumor Microenvironment / immunology

Substances

  • Basic-Leucine Zipper Transcription Factors
  • Batf protein, mouse
  • Socs1 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Ribonucleases
  • Zc3h12a protein, mouse
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • Ptpn2 protein, mouse