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Cited by 1,052Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

CD8+ T cell differentiation and dysfunction in cancer

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Philip, Mary, Schietinger, Andrea·2022·Nature Reviews Immunology
DOI 10.1038/s41577-021-00574-3PMC PMC9792152
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Abstract

CD8+ T cells specific for cancer cells are detected within tumours. However, despite their presence, tumours progress. The clinical success of immune checkpoint blockade and adoptive T cell therapy demonstrates the potential of CD8+ T cells to mediate antitumour responses; however, most patients with cancer fail to achieve long-term responses to immunotherapy. Here we review CD8+ T cell differentiation to dysfunctional states during tumorigenesis. We highlight similarities and differences between T cell dysfunction and other hyporesponsive T cell states and discuss the spatio-temporal factors contributing to T cell state heterogeneity in tumours. An important challenge is predicting which patients will respond to immunotherapeutic interventions and understanding which T cell subsets mediate the clinical response. We explore our current understanding of what determines T cell responsiveness and resistance to immunotherapy and point out the outstanding research questions.

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  • A similar model to TCF1hi progenitor CD8 T cells giving rise to TCF1lo differentiated progeny described in chronic viral infections and cancers applies to T1D.

    “TCF1hi progenitor CD8 T cells that give rise to TCF1lo differentiated progeny have been described in chronic viral infections and cancers3 and our study reveals that a similar model applies to T1D.”

    From An autoimmune stem-like CD8 T cell population drives type 1 diabetes (2022) · cites this paper as [3]

    The ‘Late dysfunction molecular programmes’ section reports that TCF1+ progenitor-like cells give rise to TCF1low differentiated cells in chronic viral infection. It also describes TCF1+ early dysfunctional tumour T cells differentiating into TCF1low late dysfunctional cells, but says evidence for a stable tumour-reactive progenitor population is lacking. The citation supports the differentiation pattern in cancer, not the stronger characterization of those tumour cells as established progenitors; the T1D finding is attributed to the citing authors’ own study. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • TCF1hi progenitor CD8 T cells that give rise to TCF1lo differentiated progeny have been described in chronic viral infections and cancers.

    “TCF1hi progenitor CD8 T cells that give rise to TCF1lo differentiated progeny have been described in chronic viral infections and cancers3”

    From An autoimmune stem-like CD8 T cell population drives type 1 diabetes (2022) · cites this paper as [3]

    The ‘Late dysfunction molecular programmes’ section says that TCF1+ progenitor-like CD8+ T cells give rise to TCF1low differentiated cells during chronic viral infection. For cancer, it describes TCF1+ early dysfunctional tumour-infiltrating cells differentiating into TCF1low late dysfunctional cells, but says evidence for a stable population of tumour-reactive TCF1+ progenitors within tumours is lacking. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • TOX has been described as a key driver of CD8 T cell exhaustion in tumours and chronic infections, settings of persistent antigen encounter.

    “TOX has been described as a key driver of CD8 T cell exhaustion in tumours and chronic infections, settings of persistent antigen encounter3.”

    From An autoimmune stem-like CD8 T cell population drives type 1 diabetes (2022) · cites this paper as [3]

  • In cancers or chronic viral infections, contexts in which T cells encounter persistent antigen, T cells enter a hyporesponsive state generally referred to as T cell exhaustion or dysfunction.

    “In cancers or chronic viral infections, contexts in which T cells encounter persistent antigen, T cells enter a hyporesponsive state generally referred to as T cell exhaustion or dysfunction3.”

    From An autoimmune stem-like CD8 T cell population drives type 1 diabetes (2022) · cites this paper as [3]

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Authors
Philip, M., & Schietinger, A.
Affiliations
  • Vanderbilt-Ingram Cancer Center (US)
  • Memorial Sloan Kettering Cancer Center (US)
Corresponding author
  • Philip, Mary
  • Schietinger, Andrea
ORCID
Venue
Nature Reviews Immunology
Publisher
Springer Science and Business Media LLC
Published
2021-07-12
Volume
22
Issue
4
Pages
209-223
ISSN
  • 1474-1733 (ISSN-L)
  • 1474-1741
DOI
10.1038/s41577-021-00574-3
PMC
PMC9792152
OpenAlex
W3179304282
Cited by
1,052
References
38
Citations by year
2026: 203 · 2025: 250 · 2024: 299 · 2023: 187 · 2022: 96 · 2021: 17
FWCI
18.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (U54CA209975, P50CA098131, DP2CA225212)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK058404)
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, T cell differentiation, T cell dysfunction, tumor immunology, cancer immunotherapy, immune checkpoint blockade, adoptive T cell therapy, immunotherapy resistance, T cell responsiveness, antitumor immunity, carcinogenesis
MeSH terms
Cell Differentiation, Humans, Immunotherapy, Lymphocyte Activation, Neoplasms, CD8-Positive T-Lymphocytes

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