英国弗朗西斯·克里克研究所Francesca D. Ciccarelli研究组发现，一种持续的干扰素高免疫表型，定义出结直肠癌对免疫疗法的反应。这一研究成果于2025年1月16日在线发表在国际学术期刊《癌细胞》上。

研究人员表示，不到50%的缺失错配修复（dMMR）结直肠癌（CRC）转移患者，对免疫检查点抑制（ICI）有反应。识别和扩展这一患者群体仍然是一个紧迫的临床需求。

研究人员报告了一种富含细胞毒性淋巴细胞和抗原呈递巨噬细胞的，局部干扰素高免疫表型是反应所必需的。该免疫表型并非dMMR CRC特有，而是包括了一部分MMR功能正常（pMMR）CRC患者。

单细胞空间分析和体外细胞共培养表明，产生干扰素的细胞毒性T细胞诱导了，相邻巨噬细胞和肿瘤细胞中过度表达抗原呈递分子，包括MHC II类不变链CD74。表达高水平CD74的dMMR CRC患者对ICI有反应，而部分CD74高表达的pMMR CRC患者，在接受ICI治疗时表现出更好的无进展生存期。

因此，CD74的丰度可以识别出，决定CRC临床获益的持续性干扰素高免疫表型，而不依赖于肿瘤突变负荷或MMR状态。

附：英文原文

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

Author: 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, 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 D. Ciccarelli

Issue&Volume: 2025-01-16

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.

DOI: 10.1016/j.ccell.2024.12.008

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00483-5