In vivo dendritic cell reprogramming for cancer immunotherapy

Science. 2024 Oct 18;386(6719):eadn9083. doi: 10.1126/science.adn9083. Epub 2024 Oct 18.

Abstract

Immunotherapy can lead to long-term survival for some cancer patients, yet generalized success has been hampered by insufficient antigen presentation and exclusion of immunogenic cells from the tumor microenvironment. Here, we developed an approach to reprogram tumor cells in vivo by adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3, which enabled them to present antigens as type 1 conventional dendritic cells. Reprogrammed tumor cells remodeled their tumor microenvironment, recruited, and expanded polyclonal cytotoxic T cells; induced tumor regressions; and established long-term systemic immunity in multiple mouse melanoma models. In human tumor spheroids and xenografts, reprogramming to immunogenic dendritic-like cells progressed independently of immunosuppression, which usually limits immunotherapy. Our study paves the way for human clinical trials of in vivo immune cell reprogramming for cancer immunotherapy.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Antigen Presentation
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Cell Line, Tumor
  • Cellular Reprogramming Techniques*
  • Cellular Reprogramming* / immunology
  • Dendritic Cells* / cytology
  • Dendritic Cells* / immunology
  • Humans
  • Immunotherapy* / methods
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism
  • Melanoma / immunology
  • Melanoma / therapy
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / therapy
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms* / immunology
  • Neoplasms* / therapy
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • T-Lymphocytes, Cytotoxic* / immunology
  • Trans-Activators / genetics
  • Tumor Microenvironment* / immunology

Substances

  • Basic-Leucine Zipper Transcription Factors
  • interferon regulatory factor-8
  • Interferon Regulatory Factors
  • proto-oncogene protein Spi-1
  • Repressor Proteins
  • SNFT protein, mouse
  • Trans-Activators