Single cell dynamics of tumor specificity vs bystander activity in CD8+ T cells define the diverse immune landscapes in colorectal cancer
Open accessAbstract
CD8+ T cell activation via immune checkpoint blockade (ICB) is successful in microsatellite instable (MSI) colorectal cancer (CRC) patients. By comparison, the success of immunotherapy against microsatellite stable (MSS) CRC is limited. Little is known about the most critical features of CRC CD8+ T cells that together determine the diverse immune landscapes and contrasting ICB responses. Hence, we pursued a deep single cell mapping of CRC CD8+ T cells on transcriptomic and T cell receptor (TCR) repertoire levels in a diverse patient cohort, with additional surface proteome validation. This revealed that CRC CD8+ T cell dynamics are underscored by complex interactions between interferon-γ signaling, tumor reactivity, TCR repertoire, (predicted) TCR antigen-specificities, and environmental cues like gut microbiome or colon tissue-specific ‘self-like’ features. MSI CRC CD8+ T cells showed tumor-specific activation reminiscent of canonical ‘T cell hot’ tumors, whereas the MSS CRC CD8+ T cells exhibited tumor unspecific or bystander-like features. This was accompanied by inflammation reminiscent of ‘pseudo-T cell hot’ tumors. Consequently, MSI and MSS CRC CD8+ T cells showed overlapping phenotypic features that differed dramatically in their TCR antigen-specificities. Given their high discriminating potential for CD8+ T cell features/specificities, we used the single cell tumor-reactive signaling modules in CD8+ T cells to build a bulk tumor transcriptome classification for CRC patients. This “Immune Subtype Classification” (ISC) successfully distinguished various tumoral immune landscapes that showed prognostic value and predicted immunotherapy responses in CRC patients. Thus, we deliver a unique map of CRC CD8+ T cells that drives a novel tumor immune landscape classification, with relevance for immunotherapy decision-making.
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In pMMR/MSS colorectal cancer, interferon gamma-positive activated T cells exist but display a less diverse T cell receptor repertoire and reduced neo-antigen reactivity, resulting in tumour-unspecific, bystander immune activity compared with dMMR/MSI colorectal cancer.
“In fact, in pMMR/MSS CRC, interferon gamma-positive activated T cells exist but display a less diverse T cell receptor repertoire and reduced neo-antigen reactivity, resulting in a tumour-unspecific, bystander immune activity when compared with dMMR/MSI CRC.120”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [120]
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- Authors
- Borràs, D. M., Verbandt, S., Ausserhofer, M., Sturm, G., Lim, J., Verge, G. A., Vanmeerbeek, I., Laureano, R. S., Govaerts, J., Sprooten, J., Hong, Y., Wall, R., De Hertogh, G., Sagaert, X., Bislenghi, G., D’Hoore, A., Wolthuis, A., Finotello, F., Park, W.-Y., Naulaerts, S., Tejpar, S., & Garg, A. D.
- Affiliations
- KU Leuven (BE)
- Universität Innsbruck (AT)
- Innsbruck Medical University (AT)
- Samsung Medical Center (KR)
- Universitair Ziekenhuis Leuven (BE)
- Corresponding author
- Tejpar, Sabine
- Garg, Abhishek D.
- ORCID
- Borràs, Daniel Morales
- Verbandt, Sara
- Sturm, Gregor
- Lim, Jinyeong
- Vanmeerbeek, Isaure
- Laureano, Raquel S.
- Govaerts, Jannes
- Sprooten, Jenny
- Hong, Yourae
- Wall, Rebecca
- Sagaert, Xavier
- Bislenghi, Gabriele
- D’Hoore, André
- Wolthuis, Albert
- Finotello, Francesca
- Park, Woong-Yang
- Naulaerts, Stefan
- Tejpar, Sabine
- Garg, Abhishek D.
- Venue
- Cell Discovery
- Published
- 2023-11-15
- Volume
- 9
- Issue
- 1
- Pages
- 114-114
- ISSN
- 2056-5968 (ISSN-L)
- PMC
- PMC10652011
- OpenAlex
- W4388687539
- Cited by
- 67
- References
- 135
- Citations by year
- 2026: 24 · 2025: 19 · 2024: 23 · 2023: 1
- FWCI
- 8.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Discovery (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Lirias (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Research Foundation (NRF-2017M3A9A7050803)
- Österreichischen Akademie der Wissenschaften
- Austrian Science Fund (T 974, 974-B30)
- Fonds Wetenschappelijk Onderzoek (G0C9620N, 1S06821N, G0B4620N, 1S44123N, 30837538)
- KU Leuven (C3/21/037, C14/19, C24M/22/055)
- Oesterreichische Nationalbank (18496)
- Vlaamse Interuniversitaire Raad
- Kom op tegen Kanker (12699)
- Vlaamse regering
- Fondation contre le Cancer
- VLIRUOS (iBOF/21/048)
- Stand Up To Cancer
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- colorectal cancer, CD8+ T cells, tumor immune landscape, microsatellite instability, microsatellite stable colorectal cancer, immune checkpoint blockade, T cell receptor repertoire, interferon-gamma signaling, tumor reactivity, bystander T cells, gut microbiota, immunotherapy response prediction, prognostic factors
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