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

DC Binder, B Engels, A Arina, P Yu, JM Slauch… - Cancer immunology …, 2013 - AACR
DC Binder, B Engels, A Arina, P Yu, JM Slauch, YX Fu, T Karrison, B Burnette, C Idel…
Cancer immunology research, 2013AACR
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 (A1-R) to increase antigen …
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 (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 show a powerful new therapeutic approach to rescue dysfunctional endogenous tumor-specific CD8+ T cells and eradicate advanced immunogenic tumors. Cancer Immunol Res; 1(2); 123–33. ©2013 AACR.
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