Subsets of human tumors are infiltrated with tumor antigen-specific CD8+ T cells (TIL), yet despite this infiltration, tumors progress. TIL are thought to be inactivated by the immunosuppressive tumor microenvironment, especially through the engagement of inhibitory receptors such as CTLA-4 and PD-1. Antibodies that block CTLA-4, PD-1, or PD-L1 can enhance the ability of CD8+ TIL to control tumors, and have had great success in leading to durable responses in cancer patients. However, not all patients respond to these therapies, even when TIL are present. Combination immunotherapy is one strategy being tested to improve immunotherapy response rates. We have recently found that the co-stimulatory receptor 4-1BB is expressed on a subset of antigen-specific CD8+ TIL. Agonist antibodies that stimulate 4-1BB have led to tumor regression in pre-clinical studies. Therefore, we set out to test whether agonist 4-1BB could synergize with blockade of PD-L1 or CTLA-4, and to study the mechanisms of synergy. Unexpectedly, we found that CD8+ TIL actively proliferate and undergo apoptosis, leading to a cycle of CD8+ TIL activation and death. Agonist 4-1BB synergized with blockade of PD-L1 or CTLA-4 not through increasing TIL proliferation, but through decreasing CD8+ TIL apoptosis, which led to a remarkable accumulation of antigen-specic CD8+ TIL. Gene expression profiling and experiments with transgenic mice suggest that increased NF-kB signaling in CD8+ TIL was responsible for many effects of anti-4-1BB immunotherapy. Additionally, we found that endogenous 4-1BB signals promoted accumulation of CD8+ TIL during the endogenous anti-tumor immune response. 4-1BB signaling in T cells was required for the efficacy of anti-PD-L1 antibodies, and the deletion of dendritic cells led to failure of anti-PD-L1 immunotherapy. Our data suggest that co-stimulation through 4-1BB is critical to counter antigen-driven apoptosis of CD8+ TIL, and for the effectiveness of anti-PD-L1 immunotherapy. Strategies to maximize co-stimulation in the tumor microenvironment and inhibit TIL apoptosis should be considered in the development of cancer immunotherapies.




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