CD103+ cDC1 and endogenous CD8+ T cells are necessary for improved CD40L-overexpressing CAR T cell antitumor function

Nat Commun. 2020 Dec 2;11(1):6171. doi: 10.1038/s41467-020-19833-3.


While effective in specific settings, adoptive chimeric antigen receptor (CAR) T cell therapy for cancer requires further improvement and optimization. Our previous results show that CD40L-overexpressing CAR T cells mobilize endogenous immune effectors, resulting in improved antitumor immunity. However, the cell populations required for this protective effect remain to be identified. Here we show, by analyzing Batf3-/- mice lacking the CD103+ conventional dendritic cell type 1 (cDC1) subpopulation important for antigen cross-presentation, that CD40L-overexpressing CAR T cells elicit an impaired antitumor response in the absence of cDC1s. We further find that CD40L-overexpressing CAR T cells stimulate tumor-resident CD11b-CD103- double-negative (DN) cDCs to proliferate and differentiate into cDC1s in wild-type mice. Finally, re-challenge experiments show that endogenous CD8+ T cells are required for protective antitumor memory in this setting. Our findings thus demonstrate the stimulatory effect of CD40L-overexpressing CAR T cells on innate and adaptive immune cells, and provide a rationale for using CD40L-overexpressing CAR T cells to improve immunotherapy responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Animals
  • Antigen Presentation
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Basic-Leucine Zipper Transcription Factors / deficiency
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / immunology
  • CD11b Antigen / deficiency
  • CD11b Antigen / genetics
  • CD11b Antigen / immunology
  • CD40 Ligand / genetics*
  • CD40 Ligand / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Female
  • Gene Expression
  • Immunity, Innate
  • Immunophenotyping
  • Immunotherapy, Adoptive / methods*
  • Integrin alpha Chains / deficiency
  • Integrin alpha Chains / genetics
  • Integrin alpha Chains / immunology
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / immunology
  • Lymphoma, B-Cell / pathology
  • Lymphoma, B-Cell / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Neoplasm Transplantation
  • Receptors, Chimeric Antigen / genetics*
  • Receptors, Chimeric Antigen / immunology
  • Repressor Proteins / deficiency
  • Repressor Proteins / genetics
  • Repressor Proteins / immunology


  • Antigens, CD
  • Basic-Leucine Zipper Transcription Factors
  • CD11b Antigen
  • Integrin alpha Chains
  • Itgam protein, mouse
  • Receptors, Chimeric Antigen
  • Repressor Proteins
  • SNFT protein, mouse
  • alpha E integrins
  • CD40 Ligand