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

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-01-16 DOI:10.1016/j.ccell.2024.12.008

Amelia Acha-Sagredo, 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, Francesca D. Ciccarelli

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引用次数: 0

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.

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.