Blockade of CTLA-4 and PD-1 enhances adoptive t-cell therapy efficacy in an ICOS-mediated manner

Lewis Zhichang Shi, Sangeeta Goswami, Tihui Fu, Baoxiang Guan, Jianfeng Chen, Liangwen Xiong, Jan Zhang, Derek Ng Tang, Xuejun Zhang, Luis M Vence, Jorge Blando, James P. Allison, Renata Collazo, Jianjun Gao, Padmanee Sharma

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Adoptive transfer of tumor-reactive T cells (ACT) has led to modest clinical benefit in the treatment of solid tumors. Failures with this therapy are primarily due to inadequate infiltration and poor function of adoptively transferred cells in the tumor microenvironment. To improve the efficacy of ACT, we combined ACT with dual blockade of CTLA-4 and PD-1. Treatment with anti-CTLA-4 plus anti-PD-1 compared with monotherapy resulted in durable antitumor responses, enhanced effector function of ACT, utilizing PMEL-1 transgenic (Tg+) CD8+ T cells, and improved survival. Using PMEL-1ICOS-/- mice, we showed that deletion of the inducible T-cell costimulator (ICOS) receptor abolished the therapeutic benefits, with selective downregulation of Eomesodermin (Eomes), interferon gamma (IFNγ), and perforin. Higher expression of IFNγ and Eomes was noted in human ICOShi CD8+ T cells compared with ICOSlow counterparts. Together, our data provide direct evidence that ACT combined with immune-checkpoint therapy confers durable antitumor responses, which largely depended on CD8+ T-cell-intrinsic expression of ICOS. Our study provides a foundation of testing combinatorial therapy of ACT of CD8 T cells and dual blocking of CTLA-4 and PD-1 in patients with melanoma.

Original languageEnglish (US)
Pages (from-to)1803-1812
Number of pages10
JournalCancer Immunology Research
Volume7
Issue number11
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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  • Cite this

    Shi, L. Z., Goswami, S., Fu, T., Guan, B., Chen, J., Xiong, L., Zhang, J., Tang, D. N., Zhang, X., Vence, L. M., Blando, J., Allison, J. P., Collazo, R., Gao, J., & Sharma, P. (2019). Blockade of CTLA-4 and PD-1 enhances adoptive t-cell therapy efficacy in an ICOS-mediated manner. Cancer Immunology Research, 7(11), 1803-1812. https://doi.org/10.1158/2326-6066.CIR-18-0873