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Cited by 334Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors

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Brummelman, Jolanda, Mazza, Emilia M.C., Alvisi, Giorgia, Colombo, Federico S., Grilli, Andrea, Mikulak, Joanna, Mavilio, Domenico, Alloisio, Marco +5 more·2018·Journal of Experimental Medicine
DOI 10.1084/jem.20180684PMC PMC6170179
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Abstract

CD8+ T cells infiltrating tumors are largely dysfunctional, but whether a subset maintains superior functionality remains ill defined. By high-dimensional single cell analysis of millions of CD8+ T cells from 53 individuals with lung cancer, we defined those subsets that are enriched in tumors compared with cancer-free tissues and blood. Besides exhausted and activated cells, we identified CXCR5+ TIM-3– CD8+ T cells with a partial exhausted phenotype, while retaining gene networks responsible for stem-like plasticity and cytotoxicity, as revealed by single cell sequencing of the whole transcriptome. Ex vivo, CXCR5+ TIM-3– CD8+ T cells displayed enhanced self-renewal and multipotency compared with more differentiated subsets and were largely polyfunctional. Analysis of inhibitory and costimulatory receptors revealed PD-1, TIGIT, and CD27 as possible targets of immunotherapy. We thus demonstrate a hierarchy of differentiation in the context of T cell exhaustion in human cancer similar to that of chronically infected mice, which is further shown to disappear with disease progression.

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  • Single-cell sequencing has identified CD8+ T cell subsets with variable exhaustion levels in cancers, including terminal exhausted T (tTex) cells, TCF7+ progenitor exhausted T (Tpex) cells, GZMK+ effector/effector memory T (Teff/Tem) cells, and CXCL13+ Tpex cells.

    “Singe-cell sequencing has identified CD8+ T cell subsets with variable exhaustion levels in cancers, including terminal exhausted T (tTex) cells, TCF7+ progenitor exhausted T (Tpex) cells,”

    From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [25]

    The Results section (“Single cell transcriptomics defines the memory identity and direct cytotoxic potential of CXCR5+ CD8+ T cells”; page not available) identifies TCF7-expressing, stem-like CD8+ tumor-infiltrating cells and more exhausted TIM-3+ cells. It does not identify the four subsets as listed: GZMK is reported in the stem-like cells rather than as a separate GZMK+ Teff/Tem subset, and the passages do not identify a CXCL13+ Tpex subset. (LLM, conf=0.87)

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Authors
Brummelman, J., Mazza, E. M. C., Alvisi, G., Colombo, F. S., Grilli, A., Mikulak, J., Mavilio, D., Alloisio, M., Ferrari, F., Lopci, E., Novellis, P., Veronesi, G., & Lugli, E.
Affiliations
  • Humanitas University (IT)
  • University of Modena and Reggio Emilia (IT)
  • IFOM (IT)
  • Nuclear Medicine Department, Humanitas Clinical and Research Hospital, Milan, Italy 9
Corresponding author
Lugli, Enrico
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2018-08-28
Volume
215
Issue
10
Pages
2520-2535
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20180684
PMC
PMC6170179
OpenAlex
W2889555301
Cited by
334
References
61
Citations by year
2026: 23 · 2025: 37 · 2024: 40 · 2023: 44 · 2022: 41 · 2021: 60 · 2020: 53 · 2019: 34 · 2018: 2
FWCI
14.00
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
Funders
  • AIRC (IG20607, IG14687, MFAG189323)
  • Bristol Myers Squibb (CA209-9YM)
  • Italian Ministry of Health (PE-2016-02363915, 82/2015)
  • Humanitas
  • Fondazione Umberto Veronesi
  • International Society for the Advancement of Cytometry
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
CD8+ T cells, tumor-infiltrating lymphocytes, T cell exhaustion, stem-like T cells, cytotoxicity, lung cancer, PD-1, TIGIT, CD27, immunotherapy targets, T cell plasticity, self-renewal
MeSH terms
Hepatitis A Virus Cellular Receptor 2, Animals, Female, Humans, Lung Neoplasms, Male, Neoplasm Proteins, Receptors, Immunologic, Stem Cells, Tumor Necrosis Factor Receptor Superfamily, Member 7, CD8-Positive T-Lymphocytes, Mice, Receptors, CXCR5

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