Search

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 invariant chain CD74. dMMR CRCs expressing high levels of CD74 respond to ICI and a subset of CD74 high pMMR CRC patients show better progression free survival when treated with ICI. Therefore, CD74 abundance can identify the constitutive interferon-high immunophenotype determining clinical benefit in CRC, independently of tumor mutational burden or MMR status. [Display omitted] • CRCs can be grouped into IFN-high or low immunophenotype based on 7 gene signatures • CRC patients responding to immunotherapy have IFN-high immunophenotype • IFN-high CRCs show high T cell-induced CD74 expression in TAMs and cancer cells • CD74 abundance predicts clinical benefit in ICI-treated dMMR and pMMR CRCs Acha-Sagredo et al. stratify colorectal cancers using features of an immune-reactive tumor microenvironment. This microenvironment, locally abundant in cytotoxic lymphocytes and antigen-presenting macrophages, facilitates immunotherapy response and is characterized by CD74 abundance. Using standard IHC, high CD74 identifies patients benefitting from immune-checkpoint inhibition therapies, independently of TMB or microsatellite status. [ABSTRACT FROM AUTHOR]