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Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion.

Publication ,  Journal Article
Gong, W; Donnelly, CR; Heath, BR; Bellile, E; Donnelly, LA; Taner, HF; Broses, L; Brenner, JC; Chinn, SB; Ji, R-R; Wen, H; Nör, JE; Wang, J ...
Published in: Oncoimmunology
2021

Type-I interferon (IFN-I) signaling is critical to maintaining antigen-presenting cell function for anti-tumor immunity. However, recent studies have suggested that IFN-I signaling may also contribute to more aggressive phenotypes, raising the possibility that IFN-I downstream signaling in cancer and myeloid cells may exert dichotomous functions.We analyzed the clinicopathologic correlation of cancer-specific IFN-I activation in 195 head and neck squamous cell carcinoma patients. We also characterized the immune impact of IFN-I receptor (IFNAR1)-deficiency in syngeneic tumor models using biochemistry, flow cytometry, and single-cell RNA-Seq. We stained HNSCC tissue microarrays with a sensitive IFN-I downstream signaling activation marker, MX1, and quantitated cancer cell-specific MX1 staining. Kaplan-Meier analysis revealed that MX1-high tumors exhibited worse survival, a phenotype that depends on the number of CD8+ intratumoral T-cells. We found that cancer-specific IFNAR1 engagement promotes cancer stemness and higher expression levels of suppressive immune checkpoint receptor ligands in cancer-derived exosomes. Notably, mice bearing Ifnar1-deficient tumors exhibited lower tumor burden, increased T-cell infiltration, reduced exhausted CD4+PD1high T-cells, and increased effector population CD8+IFN-γ+ T-cells. Then, we performed single-cell RNA-sequencing and discovered that cancer-specific IFN-I signaling not only restricts effector cells expansion but also dampens their functional fitness.The beneficial role of IFN-I activation is largely dependent on the myeloid compartment. Cancer-specific IFN-I receptor engagement promotes cancer stemness and the release of cancer-derived exosomes with high expression levels of immune checkpoint receptor ligands. Cancer-specific IFN-I activation is associated with poor immunogenicity and worse clinical outcomes in HNSCC.

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Published In

Oncoimmunology

DOI

EISSN

2162-402X

Publication Date

2021

Volume

10

Issue

1

Start / End Page

1997385

Location

United States

Related Subject Headings

  • Squamous Cell Carcinoma of Head and Neck
  • Signal Transduction
  • Mice
  • Humans
  • Head and Neck Neoplasms
  • CD8-Positive T-Lymphocytes
  • Animals
  • 3211 Oncology and carcinogenesis
  • 3204 Immunology
  • 1112 Oncology and Carcinogenesis
 

Citation

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Gong, W., Donnelly, C. R., Heath, B. R., Bellile, E., Donnelly, L. A., Taner, H. F., … Lei, Y. L. (2021). Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion. Oncoimmunology, 10(1), 1997385. https://doi.org/10.1080/2162402X.2021.1997385
Gong, Wang, Christopher R. Donnelly, Blake R. Heath, Emily Bellile, Lorenza A. Donnelly, Hülya F. Taner, Luke Broses, et al. “Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion.Oncoimmunology 10, no. 1 (2021): 1997385. https://doi.org/10.1080/2162402X.2021.1997385.
Gong W, Donnelly CR, Heath BR, Bellile E, Donnelly LA, Taner HF, et al. Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion. Oncoimmunology. 2021;10(1):1997385.
Gong, Wang, et al. “Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion.Oncoimmunology, vol. 10, no. 1, 2021, p. 1997385. Pubmed, doi:10.1080/2162402X.2021.1997385.
Gong W, Donnelly CR, Heath BR, Bellile E, Donnelly LA, Taner HF, Broses L, Brenner JC, Chinn SB, Ji R-R, Wen H, Nör JE, Wang J, Wolf GT, Xie Y, Lei YL. Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion. Oncoimmunology. 2021;10(1):1997385.

Published In

Oncoimmunology

DOI

EISSN

2162-402X

Publication Date

2021

Volume

10

Issue

1

Start / End Page

1997385

Location

United States

Related Subject Headings

  • Squamous Cell Carcinoma of Head and Neck
  • Signal Transduction
  • Mice
  • Humans
  • Head and Neck Neoplasms
  • CD8-Positive T-Lymphocytes
  • Animals
  • 3211 Oncology and carcinogenesis
  • 3204 Immunology
  • 1112 Oncology and Carcinogenesis