Chen et al. found that blockade of B7-H1 (PD-L1) on DCs, either via knockout, anti-PD-L1, or anti-PD-1 antibody, enhances the cytotoxic T lymphocyte (CTL) response to dominant antigens, but diminishes response to subdominant antigens, leading to immune escape of tumors. Similar to its effect on tumor cells, expression of B7-H1 protects DCs from lysis by CTLs and helps maintain a diverse CTL response by allowing for priming of subdominant T cell clones, which require a longer stimulation time. These findings provide a possible mechanism for tumor recurrence in PD-1 blockade and have implications for vaccine design.

Induced B7-H1 expression in the tumor microenvironment initiates adaptive resistance, which impairs immune functions and leads to tumor escape from immune destruction. Antibody blockade of the B7-H1/PD-1 interaction overcomes adaptive resistance, leading to regression of advanced human cancers and survival benefits in a significant fraction of patients. In addition to cancer cells, B7-H1 is expressed on dendritic cells (DCs), but its role in DC functions is less understood. DCs can present multiple antigens (Ags) to stimulate dominant or subdominant T cell responses. Here, we show that immunization with multiple tumor Ag-loaded DCs, in the absence of B7-H1, vastly enhances cytotoxic T lymphocyte (CTL) responses to dominant Ag. In sharp contrast, CTL responses to subdominant Ag were paradoxically suppressed, facilitating outgrowth of tumor variants carrying only subdominant Ag. Suppressed CTL responses to subdominant Ag are largely due to the loss of B7-H1-mediated protection of DCs from the lysis of CTL against dominant Ag. Therefore, B7-H1 expression on DCs may help maintain the diversity of CTL responses to multiple tumor Ags. Interestingly, a split immunization approach, which presents dominant and subdominant Ags with different DCs, promoted CTL responses to all Ags and prevented tumor escape in murine tumor models. These findings have implications for the design of future combination cancer immunotherapies.

Author Info: (1) Institute of Immunotherapy, Fujian Medical University, Fuzhou 350122, Peoples' Republic of China. Laboratory of Immunotherapy, Sun Yat-Sen University, Guangzhou 510080, Peoples' Republic of China

Author Info: (1) Institute of Immunotherapy, Fujian Medical University, Fuzhou 350122, Peoples' Republic of China. Laboratory of Immunotherapy, Sun Yat-Sen University, Guangzhou 510080, Peoples' Republic of China. (2) Department of Oncology, Johns Hopkins University, Baltimore, MD 21218. (3) Laboratory of Immunotherapy, Sun Yat-Sen University, Guangzhou 510080, Peoples' Republic of China. (4) Laboratory of Immunotherapy, Sun Yat-Sen University, Guangzhou 510080, Peoples' Republic of China. (5) Institute of Immunotherapy, Fujian Medical University, Fuzhou 350122, Peoples' Republic of China. Laboratory of Immunotherapy, Sun Yat-Sen University, Guangzhou 510080, Peoples' Republic of China. (6) Institute of Immunotherapy, Fujian Medical University, Fuzhou 350122, Peoples' Republic of China; lieping.chen@yale.edu. Laboratory of Immunotherapy, Sun Yat-Sen University, Guangzhou 510080, Peoples' Republic of China. Department of Oncology, Johns Hopkins University, Baltimore, MD 21218. Department of Immunobiology, Yale University, New Haven, CT 06520.

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