PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines

Weiyi Peng, Chengwen Liu, Chunyu Xu, Yanyan Lou, Jieqing Chen, Yan Yang, Hideo Yagita, Willem W. Overwijk, Gregory Lizeé, Laszlo Radvanyi, Patrick Hwu

Research output: Contribution to journalArticle

205 Scopus citations

Abstract

Adoptive cell transfer (ACT) is considered a promising modality for cancer treatment, but despite ongoing improvements, many patients do not experience clinical benefits. The tumor microenvironment is an important limiting factor in immunotherapy that has not been addressed fully in ACT treatments. In this study, we report that upregualtion of the immunosuppressive receptor programmed cell death-1 (PD-1) expressed on transferred T cells at the tumor site, in a murine model of ACT, compared with its expression on transferred T cells present in the peripheral blood and spleen. As PD-1 can attenuate T-cell-mediated antitumor responses, we tested whether its blockade with an anti-PD-1 antibody could enhance the antitumor activity of ACT in this model. Cotreatment with both agents increased the number of transferred T cells at the tumor site and also enhanced tumor regressions, compared with treatments with either agent alone. While anti-PD-1 did not reduce the number of immunosuppressive regulatory T cells and myeloid-derived suppressor cells present in tumor-bearing mice, we found that it increased expression of IFN-γ and CXCL10 at the tumor site. Bone marrow-transplant experiments using IFN-γ R-/- mice implicated IFN-γ as a crucial nexus for controlling PD-1-mediated tumor in filtration by T cells. Taken together, our results imply that blocking the PD-1 pathway can increase IFN-γ at the tumor site, thereby increasing chemokine-dependent trafficking of immune cells into malignant disease sites.

Original languageEnglish (US)
Pages (from-to)5209-5218
Number of pages10
JournalCancer research
Volume72
Issue number20
DOIs
StatePublished - Oct 15 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Peng, W., Liu, C., Xu, C., Lou, Y., Chen, J., Yang, Y., Yagita, H., Overwijk, W. W., Lizeé, G., Radvanyi, L., & Hwu, P. (2012). PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. Cancer research, 72(20), 5209-5218. https://doi.org/10.1158/0008-5472.CAN-12-1187