Abstract A088: Increase lymphocyte infiltration overcomes tumor resistance to checkpoint blockade

Abstract

Abstract Spontaneous T cell-inflamed tumor microenvironment is associated with clinical responses to immunotherapies, including immune checkpoint blockades. However, majority of established tumors often inhibit peripheral T cells entering tumor tissues for tumor destruction and/or prevent effective T cell priming. Previous studies in our lab have shown that upregulation of the tumor necrosis factor superfamily member LIGHT (also known as TNFSF14) in peripheral tissues results in T cell activation and migration into non-lymphoid tissues and formation of lymphoid-like structures, which lead to rapid T cell-mediated tissue destruction. Furthermore, local expression of LIGHT by tumor cells may promote the formation of lymphoid-like structures for direct T-cell sequestration and activation, leading to tumor regression. Those data suggest LIGHT as an interesting candidate to create T cell-inflamed tumor environment. To better evaluate the therapeutic efficacy of human LIGHT protein in both murine and human systems, we engineered human LIGHT by random mutation using yeast-display system, and were able to generate a human LIGHT mutant which binds to both murine and human receptors while remains stable. To specifically target LIGHT to tumor tissues, an antibody-LIGHT fusion protein was generated. In different mouse models, we found that antibody-LIGHT induces a T cell inflamed tumor environment. This is correlated with an upregulation of inflammatory cytokines and adhesion molecules, and leads to the rejection of established tumors. More importantly, we observed that LIGHT-mediated T cell inflamed environment is critical for restoring the efficacy of checkpoint blockade therapy. When we blocked lymphocyte trafficking, a tumor previously responding to checkpoint blockade became resistant to therapy. This process can be reversed by treating with LIGHT. Our study indicates that targeting LIGHT may be an effective strategy for cancer immunotherapy, especially those who do not response to checkpoint blockade due to the lack of infiltration. Citation Format: Haidong Tang, Yang Wang, Yang-Xin Fu. Increase lymphocyte infiltration overcomes tumor resistance to checkpoint blockade. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A088.