Creating a T cell-inflamed tumor microenvironment overcomes resistance to checkpoint blockade

Abstract

Abstract Recent clinical trials with checkpoint blockade antibodies have shown unprecedented durable responses in some patients with a variety of cancers. However, such therapies fail to induce responses in majority of cancer patients. How to increase the objective response rate becomes an urgent challenge. A T cell-inflamed tumor microenvironment is associated with clinical responses to immunotherapies, including checkpoint blockades. Previous studies in our lab have shown that local expression of the tumor necrosis factor superfamily member LIGHT (also known as TNFSF14) by tumor cells may promote the formation of lymphoid-like structures for direct T-cell sequestration and activation, leading to tumor regression. To better evaluate the therapeutic efficacy of LIGHT, we target LIGHT to tumor tissues through an antibody-LIGHT fusion protein. We demonstrated that targeting tumors with LIGHT activates lymphotoxin b receptor signaling, leading to the production of chemokines that recruit massive numbers of T cells. Furthermore, targeting non-T cell-inflamed tumor tissues by antibody-guided LIGHT creates a T cell-inflamed microenvironment and overcomes tumor resistance to checkpoint blockade. 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.