LIGHTing tumor up for checkpoint blockade

Immune checkpoint blockade, as a breakthrough in cancer therapy with anti-PD-L1, anti-PD-1, and anti-CTLA4, has demonstrated impressive therapeutic effects in multiple clinical trials. However, only a small minority of patients respond to such therapies [1]. Higher tumor infiltrating lymphocytes (TILs) and PD-L1 expression in tumors have been found to correlate with better prognoses [2, 3]. However, due to a lack of proper tumor models, it is difficult to determine the exact contributions of PD-L1 expression or TILs to checkpoint blockade therapies. In a recent study published in Cancer Cell, Tang H. et al. performed an extensive investigation to address these issues, and provided strong evidence for designing therapeutic strategies to extend the benefits of checkpoint blockade for more patients [4]. The authors first examined the correlation between PD-L1 expression and the responsiveness to PD-L1 blockade in a number of mouse tumor models, which elicited very interesting results, as observed in clinical patients. Specifically, MC38 tumors responded well to PD-L1 blockade, while Ag104Ld tumors didn't respond to the same treatment at all. Further analysis showed that both of the tumors expressed similar high levels of PD-L1, indicating that PD-L1 expression is not sufficient to determine the therapeutic effect of PD-L1 blockade. Interestingly, a significantly greater number of TILs were found in MC38 tumors. Furthermore, therapeutic effects of PD-L1 blockade in MC38 tumors were completely abolished when lymphocyte infiltration was blocked. The critical role of TILs in tumor control by PD-L1 blockade was further confirmed in several other PD-L1 expressing tumor models. It would be interesting to know whether promoting lymphocyte-infiltration into a tumor can increase the therapeutic effect of anti-PD-L1. Previous studies in the same group have shown that ectopic expression of LIGHT, a cytokine belonging to the tumor necrosis factor superfamily, is able to recruit and activate T cells in tumor tissues [5]. By interacting with lymphotoxin β receptors, LIGHT induces the production of various chemokines and adhesion molecules, which recruit immune cells. LIGHT can also provide co-stimulatory signals to T cells by binding to another receptor, herpesvirus entry mediator. However, the application of LIGHT for tumor immunotherapy in mouse models is limited due to the instability of the recombinant mouse-LIGHT protein. To overcome this issue, a mutated version of human LIGHT (hmLIGHT) was created, which can bind to both human and mouse receptors. Tumor-specific delivery of hmLIGHT has shown impressive anti-tumor effects in several different mouse models [4]. Unfortunately, …