TY - JOUR
T1 - A constitutive interferon-high immunophenotype defines response to immunotherapy in colorectal cancer
AU - Acha-Sagredo, Amelia
AU - Andrei, Pietro
AU - Clayton, Kalum
AU - Taggart, Emma
AU - Antoniotti, Carlotta
AU - Woodman, Chloé A.
AU - Afrache, Hassnae
AU - Fourny, Constance
AU - Armero, Maria
AU - Moinudeen, Hafsa Kaja
AU - Green, Mary
AU - Bhardwaj, Nisha
AU - Mikolajczak, Anna
AU - Rodriguez-Lopez, Maria
AU - Crawford, Marg
AU - Connick, Emma
AU - Lim, Steven
AU - Hobson, Philip
AU - Linares, Josep
AU - Ignatova, Ekaterina
AU - Pelka, Diana
AU - Smyth, Elizabeth C.
AU - Diamantis, Nikolaos
AU - Sosnowska, Dominika
AU - Carullo, Martina
AU - Ciraci, Paolo
AU - Bergamo, Francesca
AU - Intini, Rossana
AU - Nye, Emma
AU - Barral, Patricia
AU - Mishto, Michele
AU - Arnold, James N.
AU - Lonardi, Sara
AU - Cremolini, Chiara
AU - Fontana, Elisa
AU - Rodriguez-Justo, Manuel
AU - Ciccarelli, Francesca D.
PY - 2025/1/16
Y1 - 2025/1/16
N2 - 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.
AB - 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.
U2 - 10.1016/j.ccell.2024.12.008
DO - 10.1016/j.ccell.2024.12.008
M3 - Article
SN - 1535-6108
VL - 43
SP - 292-307.e7
JO - CANCER CELL
JF - CANCER CELL
IS - 2
ER -