Dysfunctional tumor-infiltrating Vδ1 + T lymphocytes in microsatellite-stable colorectal cancer
Although γδ T cells are known to participate in immune dysregulation in solid tumors, their relevance to human microsatellite-stable (MSS) colorectal cancer (CRC) is still undefined. Here, using integrated gene expression analysis and T cell receptor sequencing, we characterized γδ T cells in MSS CRC, with a focus on Vδ1 + T cells. We identified Vδ1<sup>+</sup> T cells with shared motifs in the third complementarity-determining region of the δ-chain, reflective of antigen recognition. Changes in gene and protein expression levels suggested a dysfunctional effector state of Vδ1<sup>+</sup> T cells in MSS CRC, distinct from Vδ1<sup>+</sup> T cells in microsatellite-instable (MSI). Interaction analysis highlighted an immunosuppressive role of fibroblasts in the dysregulation of Vδ1<sup>+</sup> T cells in MSS CRC via the TIGIT-NECTIN2 axis. Blocking this pathway with a TIGIT antibody partially restored cytotoxicity of the dysfunctional Vδ1 phenotype. These results define an operative pathway in γδ T cells in MSS CRC.
Authors
- Johannes Laengle (ORCID: https://orcid.org/0000-0003-4771-1398)
- Rudolf Oehler (ORCID: https://orcid.org/0000-0003-2891-7155)
- Lukas Watzke
- Anne B. Vogt
- Julijan Kabiljo (ORCID: https://orcid.org/0000-0002-6778-6648)
- Victoria Stary (ORCID: https://orcid.org/0000-0002-3854-9934)
- Ram Vinay Pandey (ORCID: https://orcid.org/0000-0002-2533-8687)
- Lisa Kleißl (ORCID: https://orcid.org/0000-0001-8011-796X)
- Florian Deckert (ORCID: https://orcid.org/0000-0002-3075-6808)
- Georg Stary (ORCID: https://orcid.org/0000-0003-1746-4250)
- Matthias Farlik (ORCID: https://orcid.org/0000-0003-0698-2992)
- Julia List (ORCID: https://orcid.org/0000-0002-4199-3198)
- Michael Bergmann (ORCID: https://orcid.org/0000-0001-8529-1166)
- Nina Pilat (ORCID: https://orcid.org/0000-0003-4071-9397)
- Vasileios Gerakopoulos
- Samuel W. Lukowski (ORCID: https://orcid.org/0000-0002-8598-7902)
- Hannes Stockinger (ORCID: https://orcid.org/0000-0001-6404-4430)
Institutions
- Austrian Academy of Sciences (AT)
- Comprehensive Cancer Center Vienna (AT)
- Boehringer Ingelheim (Austria) (AT)
- CeMM Research Center for Molecular Medicine (AT)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-13
- DOI
- https://doi.org/10.1038/s41467-024-51025-1
- Citations
- 23
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 6.50
Funders
- Vienna Science and Technology Fund
- Österreichischen Akademie der Wissenschaften
- Universität Wien
- Medizinische Universität Wien