Rescue of Notch-1 signaling in antigen-specific CD8+ T cells overcomes tumor-induced T-cell suppression and enhances immunotherapy in cancer

Rosa A. Sierra, Paul Thevenot, Patrick L. Raber, Yan Cui, Chris Parsons, Augusto C. Ochoa, Jimena Trillo-Tinoco, Luis Del Valle, Paulo C. Rodriguez

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

An impaired antitumor immunity is found in patients with cancer and represents a major obstacle in the successful development of different forms of immunotherapy. Signaling through Notch receptors regulates the differentiation and function of many cell types, including immune cells. However, the effect of Notch in CD8+ T-cell responses in tumors remains unclear. Thus, we aimed to determine the role of Notch signaling in CD8+ cells in the induction of tumor-induced suppression. Our results using conditional knockout mice show that Notch-1 and Notch-2 were critical for the proliferation and IFNγ production of activated CD8+ T cells and were significantly decreased in tumor-infiltrating T cells. Conditional transgenic expression of Notch-1 intracellular domain (N1IC) in antigen-specific CD8+ T cells did not affect activation or proliferation of CD8+ T cells, but induced a central memory phenotype and increased cytotoxicity effects and granzyme B levels. Consequently, a higher antitumor response and resistance to tumor-induced tolerance were found after adoptive transfer of N1IC transgenic CD8+ T cells into tumor-bearing mice. Additional results showed that myeloid-derived suppressor cells (MDSC) blocked the expression of Notch-1 and Notch-2 in T cells through nitric oxide-dependent mechanisms. Interestingly, N1IC overexpression rendered CD8+ T cells resistant to the tolerogenic effect induced by MDSC in vivo. Together, the results suggest the key role of Notch in the suppression of CD8 T-cell responses in tumors and the therapeutic potential of N1IC in antigen-specific CD8+ cells to reverse-cell suppression and increase the efficacy of T cell-based immunotherapies in cancer.

Original languageEnglish (US)
Pages (from-to)800-811
Number of pages12
JournalCancer Immunology Research
Volume2
Issue number8
DOIs
StatePublished - Aug 2014

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CD8 Antigens
Immunotherapy
T-Lymphocytes
Neoplasms
Notch Receptors
Granzymes
Adoptive Transfer
Knockout Mice
Immunity
Nitric Oxide

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Rescue of Notch-1 signaling in antigen-specific CD8+ T cells overcomes tumor-induced T-cell suppression and enhances immunotherapy in cancer. / Sierra, Rosa A.; Thevenot, Paul; Raber, Patrick L.; Cui, Yan; Parsons, Chris; Ochoa, Augusto C.; Trillo-Tinoco, Jimena; Del Valle, Luis; Rodriguez, Paulo C.

In: Cancer Immunology Research, Vol. 2, No. 8, 08.2014, p. 800-811.

Research output: Contribution to journalArticle

Sierra, RA, Thevenot, P, Raber, PL, Cui, Y, Parsons, C, Ochoa, AC, Trillo-Tinoco, J, Del Valle, L & Rodriguez, PC 2014, 'Rescue of Notch-1 signaling in antigen-specific CD8+ T cells overcomes tumor-induced T-cell suppression and enhances immunotherapy in cancer', Cancer Immunology Research, vol. 2, no. 8, pp. 800-811. https://doi.org/10.1158/2326-6066.CIR-14-0021
Sierra, Rosa A. ; Thevenot, Paul ; Raber, Patrick L. ; Cui, Yan ; Parsons, Chris ; Ochoa, Augusto C. ; Trillo-Tinoco, Jimena ; Del Valle, Luis ; Rodriguez, Paulo C. / Rescue of Notch-1 signaling in antigen-specific CD8+ T cells overcomes tumor-induced T-cell suppression and enhances immunotherapy in cancer. In: Cancer Immunology Research. 2014 ; Vol. 2, No. 8. pp. 800-811.
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