CD4+ T cell-licensed CD8+ T cells are required for immunotherapy response in MHC-I negative MMRd cancer
Abstract DNA mismatch repair deficiency (MMRd) causes hypermutation and increased T cell response in multiple tumor types. MMRd colorectal cancers (CRC) display frequent immune evasion, but respond to immune checkpoint blockade (ICB), through uncertain mechanisms. We generated mouse models of MMRd CRC, and found that accelerated tumorigenesis was accompanied by loss of major histocompatibility class I (MHC-I) expression and exclusion of cytotoxic CD8 + T cells, but not helper CD4 + T cells. MHC-I deletion (MHC-I KO ) in a syngeneic MMRd CRC model reduced tumor CD8 + but not CD4 + cell infiltrate, and accelerated tumor growth. MMRd MHC-I KO tumors were resistant to anti-PD1 ICB, but sensitive to anti-PD1 and anti-CTLA4 combination ICB (cICB) with response dependent on both CD4 + and CD8 + T cells, but not γδ-T cells. CD4 + cell depletion-induced cICB resistance was reversed by CD40 agonism, suggesting that CD4 + cells directly or indirectly license CD8 + cell for MHC-I-independent cytotoxicity. Investigation of MHC-I status as predictor of cICB vs ICB monotherapy appears worthwhile.
Authors
- Matthieu J. Miossec (ORCID: https://orcid.org/0000-0001-8148-7890)
- Annabelle Lewis (ORCID: https://orcid.org/0000-0003-1876-1927)
- Luciana Gneo (ORCID: https://orcid.org/0000-0002-1890-2665)
- Isabela Pedroza‐Pacheco (ORCID: https://orcid.org/0000-0003-4921-7940)
- Ian M. Tomlinson
- Monika Madrova (ORCID: https://orcid.org/0000-0001-6709-2307)
- Hans W. Nijman (ORCID: https://orcid.org/0000-0002-1821-3042)
- David N. Church (ORCID: https://orcid.org/0000-0002-4617-962X)
- Mingjia Xi
- Lai Mun Wang (ORCID: https://orcid.org/0000-0001-7113-4215)
- Marta Requesens (ORCID: https://orcid.org/0000-0001-5559-8845)
- Noemi Perujo Holland
- Noélia Che (ORCID: https://orcid.org/0000-0002-4817-3571)
- Floris Foijer (ORCID: https://orcid.org/0000-0003-0989-3127)
- Tijana Tomasevic
- Ibrahem Al-Obaidi (ORCID: https://orcid.org/0000-0001-9959-1637)
- Annechien Plat (ORCID: https://orcid.org/0000-0002-0789-9819)
- Yanshu Cai (ORCID: https://orcid.org/0009-0008-6814-5384)
- Marnix; id_orcid 0000-0001-9795-2267 Jansen
- Mark Glaire
- Katarzyna Kedzierska
- Marco de Bruyn
- Nienke van Rooij
- Charlotte O’Riordan-Moore
Institutions
- University Medical Center Groningen (NL)
- Centre for Human Genetics (GB)
- University of Groningen (NL)
- Sichuan University (CN)
- Churchill Hospital (GB)
- University of Oxford (GB)
- West China Hospital of Sichuan University (CN)
- University College London (GB)
- Brunel University of London (GB)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2026-10-26
- DOI
- https://doi.org/10.1038/s44321-026-00538-x
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- Cancer Research UK
- Pathological Society of Great Britain and Ireland