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 journalArticle

41 Citations (Scopus)

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

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Bacterial Vaccines
T-Lymphocytes
Antigens
Neoplasms
Blocking Antibodies
Melanoma
Tumor Microenvironment
Neoplasm Antigens
Salmonella typhimurium

Keywords

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

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Antigen-specific bacterial vaccine combined with anti-PD-L1 rescues dysfunctional endogenous T cells to reject long-established cancer. / Binder, David C.; Engels, Boris; Arina, Ainhoa; Yu, Ping; Slauch, James M.; Fu, Yang Xin; Karrison, Theodore; Burnette, Byron; Idel, Christian; Zhao, Ming; Hoffman, Robert M.; Munn, David H; Rowley, Donald A.; Schreiber, Hans.

In: Cancer Immunology Research, Vol. 1, No. 2, 01.08.2013, p. 123-133.

Research output: Contribution to journalArticle

Binder, DC, Engels, B, Arina, A, Yu, P, Slauch, JM, Fu, YX, Karrison, T, Burnette, B, Idel, C, Zhao, M, Hoffman, RM, Munn, DH, Rowley, DA & Schreiber, H 2013, 'Antigen-specific bacterial vaccine combined with anti-PD-L1 rescues dysfunctional endogenous T cells to reject long-established cancer', Cancer Immunology Research, vol. 1, no. 2, pp. 123-133. https://doi.org/10.1158/2326-6066.CIR-13-0058
Binder, David C. ; Engels, Boris ; Arina, Ainhoa ; Yu, Ping ; Slauch, James M. ; Fu, Yang Xin ; Karrison, Theodore ; Burnette, Byron ; Idel, Christian ; Zhao, Ming ; Hoffman, Robert M. ; Munn, David H ; Rowley, Donald A. ; Schreiber, Hans. / Antigen-specific bacterial vaccine combined with anti-PD-L1 rescues dysfunctional endogenous T cells to reject long-established cancer. In: Cancer Immunology Research. 2013 ; Vol. 1, No. 2. pp. 123-133.
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