A constitutive interferon-high immunophenotype defines response to immunotherapy in colorectal cancer

Fewer than 50% of metastatic deficient mismatch repair (dMMR) colorectal cancer (CRC) patients respond to immune checkpoint inhibition (ICI). Identifying and expanding this patient population remains a pressing clinical need. Here, we report that an interferon-high immunophenotype locally enriched in cytotoxic lymphocytes and antigen-presenting macrophages is required for response. This immunophenotype is not exclusive to dMMR CRCs but comprises a subset of MMR proficient (pMMR) CRCs. Single-cell spatial analysis and in vitro cell co-cultures indicate that interferon-producing cytotoxic T cells induce overexpression of antigen presentation in adjacent macrophages and tumor cells, including MHC class II…

• WT
  Wellcome Trust

  Award: FC001002
• FC
  Francis Crick Institute

  Award: FC001002
• CR
  Cancer Research UK

  Awards: C7893/A26233, FC001002, C43634/A25487, CANCTA-2023/100002, EDDPJT-Nov21\100010, 100002, EDDPJT-Nov21\u2216100010
• NI
  National Institute for Health and Care Research
• UO
  University of Oxford
• EC
  European Commission

  Award: PE_00000019
• MD
  Ministero dell’Istruzione, dell’Università e della Ricerca
• UC
  University College London Hospitals NHS Foundation Trust
• MR
  Medical Research Council

  Awards: CANCTA-2023/100002, MR/W006820/1, FC001002
• UB
  UCLH Biomedical Research Centre
• KI
  Krell Institute