A constitutive interferon-high immunophenotype defines response to immunotherapy in colorectal cancer
Amelia Acha‐Sagredo, Pietro Andrei, Kalum Clayton, Emma Taggart, Carlotta Antoniotti, Chloé Woodman, Hassnae Afrache, Constance Fourny, María Armero, Hafsa Kaja Moinudeen, Mary Green, Nisha Bhardwaj, Anna Mikolajczak, Maria Rodríguez‐López, Marg Crawford, Emma Connick, Steven Lim, Philip Hobson, Josep Linares, E. Ignatova, Diana Pelka, Elizabeth Smyth, Nikolaos Diamantis, Dominika Sosnowska, Martina Carullo, P. Ciracì, 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
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.