Antigen-specific bacterial vaccine combined with anti-PD-L1 rescues dysfunctional endogenous T cells to reject long-established cancer

David C. Binder, Boris Engels, Ainhoa Arina, Ping Yu, James M. Slauch, Yang Xin Fu, Theodore Karrison, Byron Burnette, Christian Idel, Ming Zhao, Robert M. Hoffman, David H Munn, Donald A. Rowley, Hans Schreiber

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Immunogenic tumors grow progressively even when heavily infiltrated by CD8(+) T cells. We investigated how to rescue CD8(+) T cell function in long-established immunogenic melanomas that contained a high percentage of endogenous PD-1(+) tumor-specific CD8(+) T cells that were dysfunctional. Treatment with αPD-L1 and αCTLA-4 blocking antibodies did not prevent tumors from progressing rapidly. We then tested exogenous tumor-specific antigen delivery into tumors using Salmonella Typhimurium A1-R to increase antigen levels and generate a proinflammatory tumor microenvironment. Antigen-producing A1-R rescued the endogenous tumor-specific CD8(+) T cell response: proliferation was induced in the lymphoid organs and effector function was recovered in the tumor. Treatment with antigen-producing A1-R led to improved mouse survival and resulted in 32% rejection of long-established immunogenic melanomas. Following treatment with antigen-producing A1-R, the majority of tumor-specific CD8(+) T cells still expressed a high level of PD-1 in the tumor. Combining antigen-producing A1-R with αPD-L1 blocking antibody enhanced the expansion of tumor-specific CD8(+) T cells and resulted in 80% tumor rejection. Collectively, these data demonstrate a powerful new therapeutic approach to rescue dysfunctional endogenous tumor-specific CD8(+) T cells and eradicate advanced immunogenic tumors.

Original languageEnglish (US)
Pages (from-to)123-133
Number of pages11
JournalCancer Immunology Research
Volume1
Issue number2
DOIs
StatePublished - Aug 1 2013

Keywords

  • CD8+ T cell rescue
  • PD-L1
  • S. Typhimurium
  • Tumor rejection
  • vaccine

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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