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

Cancer Immunol Res. 2013 Aug;1(2):123-33. doi: 10.1158/2326-6066.CIR-13-0058.


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.

Keywords: CD8+ T cell rescue; PD-L1; S. Typhimurium; Tumor rejection; vaccine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigen Presentation
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology*
  • Bacterial Vaccines / genetics
  • Bacterial Vaccines / immunology*
  • Bacterial Vaccines / pharmacology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cancer Vaccines / genetics
  • Cancer Vaccines / immunology*
  • Cancer Vaccines / pharmacology
  • Epitopes
  • Female
  • Lymphocyte Activation
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Ovalbumin / immunology
  • Ovalbumin / pharmacology
  • Peptide Fragments / immunology
  • Peptide Fragments / pharmacology
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology*


  • Antigens, Neoplasm
  • Bacterial Vaccines
  • Cancer Vaccines
  • Epitopes
  • OVA-8
  • Peptide Fragments
  • Programmed Cell Death 1 Receptor
  • Ovalbumin