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

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.

• Authors: 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
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 1 Issue 2 Pg. 123-33 (Aug 2013) ISSN: 2326-6074 [Electronic] United States
• PMID: 24455752 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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