IL-7 promotes CD19-directed CAR-T cells proliferation through miRNA-98-5p by targeting CDKN1A

Int Immunopharmacol. 2023 Nov;124(Pt B):110974. doi: 10.1016/j.intimp.2023.110974. Epub 2023 Sep 25.

Abstract

CAR-T targeting CD19 have achieved significant effects in the treatment of B-line leukemia and lymphoma. However, the treated patients frequently relapsed and could not achieve complete remission. Therefore, improving the proliferation and cytotoxicity of CAR-T cells, reducing exhaustion and enhancing infiltration capacity are still issues to be solved. The IL-7 has been shown to enhance the memory characteristics of CAR-T cells, but the specific mechanism has yet to be elaborated. miRNAs play an important role in T cell activity. However, whether miRNA is involved in the activation of CAR-T cells by IL-7 has not yet been reported. Our previous study had established the 3rd generation CAR-T cells. The present study further found that IL-7 significantly increased the proliferation of anti-CD19 CAR-T cells, the ratio of CD4 + CAR + cells and the S phase of cell cycle. In vivo study NAMALWA xenograft model showed that IL-7-stimulated CAR-T cells possessed stronger tumoricidal efficiency. Further we validated that IL-7 induced CAR-T cells had low expression of CDKN1A and high expression of miRNA-98-5p. Additionally, CDKN1A was associated with miRNA-98-5p. Our results, for the first time, suggested IL-7 could conspicuously enhance the proliferation of CAR-T cells through miRNA-98-5p targeting CDKN1A expression, which should be applied to CAR-T production.

Keywords: CD19-directed CAR-T cells; CDKN1A; IL-7; Immunotherapy; miRNA-98-5p.

MeSH terms

  • Antigens, CD19 / genetics
  • Antigens, CD19 / metabolism
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Humans
  • Immunotherapy, Adoptive / methods
  • Interleukin-7 / genetics
  • Interleukin-7 / metabolism
  • MicroRNAs* / genetics
  • Receptors, Chimeric Antigen* / metabolism

Substances

  • Receptors, Chimeric Antigen
  • Interleukin-7
  • MicroRNAs
  • Antigens, CD19
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • MIRN98 microRNA, human