Blockade of programmed death-1 pathway rescues the effector function of tumor-infiltrating T cells and enhances the antitumor efficacy of lentivector immunization

Qifeng Zhou, Haiyan Xiao, Yanjun Liu, Yibing Peng, Yuan Hong, Hideo Yagita, Phillip Chandler, David H. Munn, Andrew Mellor, Ning Fu, Yukai He

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Despite intensive effort, the antitumor efficacy of tumor vaccines remains limited in treating established tumors regardless of the potent systemic tumor-specific immune response and the increases of tumor infiltration of Teffector cells. In the current study, we demonstrated that although lentivector (lv) immunization markedly increased Ag-dependent tumor infiltration of CD8 and CD4 T cells and generated Ag-specific antitumor effect, it simultaneously increased the absolute number of myeloid-derived suppressor cells and regulatory T cells in the tumor lesions. In addition, lv immunization induced expression of programmed death-ligand 1 in the tumor lesions. Furthermore, the tumor-infiltrating CD8 T cells expressed high levels of programmed death-1 and were partially dysfunctional, producing lower amounts of effector cytokines and possessing a reduced cytotoxicity. Together, these immune-suppression mechanisms in the tumor microenvironment pose a major obstacle to effective tumor immunotherapy and may explain the limited antitumor efficacy of lv immunization. The loss of effector function in the tumor microenvironment is reversible, and the effector function of CD8 T cells in the tumor could be partially rescued by blocking programmed death-1 and programmed death-ligand 1 pathway in vitro and in vivo, resulting in enhanced antitumor efficacy of lv immunization. These data suggest that immunization alone may exacerbate immune suppression in the tumor lesions and that methods to improve the tumor microenvironment and to rescue the effector functions of tumor-infiltrating T cells should be incorporated into immunization strategies to achieve enhanced antitumor efficacy.

Original languageEnglish (US)
Pages (from-to)5082-5092
Number of pages11
JournalJournal of Immunology
Volume185
Issue number9
DOIs
StatePublished - Nov 1 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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