Acha-Sagredo, Andrei, and Clayton et al. used RNAseq of tumor epithelium and stroma separately to show that CRCs express an IFNhi or IFNlo profile, and that IFNhi expression by cytotoxic lymphocytes and TAMs was required for patients with CRC to respond to ICB. Single cell spatial transcriptomics and coculture assays showed that IFNγ-producing cytotoxic T cells boosted antigen presentation and CD74 (MHC-II invariant chain) expression by proximal TAMs and cancer cells. CD74hi TMEs associated with ICB responses in patients with metastatic, mismatch repair-deficient (dMMR) CRC, and in a subset of patients with MMR-proficient (pMMR) CRC.

Contributed by Paula Hochman

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.

Author Info: (1) Cancer Systems Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Centre for Cancer Evolution, Bart's Cancer Institute, Queen Mary University London, London E

Author Info: (1) Cancer Systems Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Centre for Cancer Evolution, Bart's Cancer Institute, Queen Mary University London, London EC1M 6AU, UK. (2) Cancer Systems Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Centre for Cancer Evolution, Bart's Cancer Institute, Queen Mary University London, London EC1M 6AU, UK. (3) Cancer Systems Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Centre for Cancer Evolution, Bart's Cancer Institute, Queen Mary University London, London EC1M 6AU, UK. (4) Cancer Systems Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Centre for Cancer Evolution, Bart's Cancer Institute, Queen Mary University London, London EC1M 6AU, UK. (5) Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. (6) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (7) Centre for Inflammation Biology and Cancer Immunology, King's College London, London SE1 1UL, UK; Molecular Immunology Laboratory, Francis Crick Institute, London NW1 1AT, UK. (8) Centre for Inflammation Biology and Cancer Immunology, King's College London, London SE1 1UL, UK; Molecular Immunology Laboratory, Francis Crick Institute, London NW1 1AT, UK. (9) Cancer Systems Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Centre for Cancer Evolution, Bart's Cancer Institute, Queen Mary University London, London EC1M 6AU, UK. (10) Cancer Systems Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK. (11) Experimental Histopathology, The Francis Crick Institute, London NW1 1AT, UK. (12) Experimental Histopathology, The Francis Crick Institute, London NW1 1AT, UK. (13) Experimental Histopathology, The Francis Crick Institute, London NW1 1AT, UK. (14) Advanced Sequencing Facility, The Francis Crick Institute, London NW1 1AT, UK. (15) Advanced Sequencing Facility, The Francis Crick Institute, London NW1 1AT, UK. (16) Advanced Sequencing Facility, The Francis Crick Institute, London NW1 1AT, UK. (17) Flow Cytometry Facility, The Francis Crick Institute, London NW1 1AT, UK. (18) Flow Cytometry Facility, The Francis Crick Institute, London NW1 1AT, UK. (19) Department of Histopathology, University College London Cancer Institute, London, UK. (20) Drug Development Unit, Sarah Cannon Research Institute UK, London, UK. (21) Drug Development Unit, Sarah Cannon Research Institute UK, London, UK. (22) Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LE, UK. (23) Department of Medical Oncology, Royal Free London NHS Foundation Trust, London WC1E 6BT, UK. (24) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (25) Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. (26) Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. (27) Oncology Unit 1, Department of Oncology Veneto Institute of Oncology IOV-IRCCS, Padova, Italy. (28) Oncology Unit 1, Department of Oncology Veneto Institute of Oncology IOV-IRCCS, Padova, Italy. (29) Experimental Histopathology, The Francis Crick Institute, London NW1 1AT, UK. (30) Centre for Inflammation Biology and Cancer Immunology, King's College London, London SE1 1UL, UK; Immune Responses to Lipids Laboratory, The Francis Crick Institute, London NW1 1AT, UK. (31) Centre for Inflammation Biology and Cancer Immunology, King's College London, London SE1 1UL, UK; Molecular Immunology Laboratory, Francis Crick Institute, London NW1 1AT, UK. (32) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (33) Oncology Unit 1, Department of Oncology Veneto Institute of Oncology IOV-IRCCS, Padova, Italy. (34) Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. (35) Drug Development Unit, Sarah Cannon Research Institute UK, London, UK. (36) Department of Histopathology, University College London Cancer Institute, London, UK. (37) Cancer Systems Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Centre for Cancer Evolution, Bart's Cancer Institute, Queen Mary University London, London EC1M 6AU, UK. Electronic address: f.ciccarelli@qmul.ac.uk.