A constitutive interferon-high immunophenotype defines response to immunotherapy in colorectal cancer
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Amelia Acha Pietro Andrei Kalum Clayton Emma Taggart Carlotta Antoniotti Chloé A Woodman Hassnae Afrache Constance Fourny Maria Armero Hafsa Kaja Moinudeen Mary Green Nisha Bhardwaj Anna Mikolajczak Maria Rodriguez-Lopez Marg Crawford Emma Connick Steven Lim Philip Hobson Josep Linares Ekaterina Ignatova Diana Pelka Elizabeth C Smyth Nikolaos Diamantis Dominika Sosnowska Martina Carullo Paolo Ciraci Francesca Bergamo Rossana Intini Emma Nye Patricia Barral Michele Mishto James N Arnold Sara Lonardi Chiara Cremolini Elisa Fontana Manuel Rodriguez-Justo Francesca Ciccarelli
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Abstract
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.
Journal details
Journal
Cancer Cell
Volume
43
Issue number
2
Pages
292-307 .e7
Available online
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10.1016/j.ccell.2024.12.008
Europe PubMed Central
39824178
Pubmed
39824178
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