Cited by 67Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologySingle-cell and spatial transcriptomics

Single cell dynamics of tumor specificity vs bystander activity in CD8+ T cells define the diverse immune landscapes in colorectal cancer

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Borràs, Daniel Morales, Verbandt, Sara, Ausserhofer, Markus, Sturm, Gregor, Lim, Jinyeong, Verge, Gil Arasa, Vanmeerbeek, Isaure, Laureano, Raquel S. +14 more·2023·Cell Discovery

Abstract

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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Crossref · 10.1038/s41421-023-00605-4

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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”

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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.
Venue
Cell Discovery
Published
2023-11-15
Volume
9
Issue
1
Pages
114-114
ISSN
2056-5968 (ISSN-L)
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
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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