Academia Sinica Logo

Despite the breakthrough of immune checkpoint inhibitors (ICIs), the majority of solid tumors remain immunologically "cold" and fail to respond to treatment. This immunological coldness is primarily driven by two factors: a systemic lack of tumor-specific T cells and a local, suboptimal inflammatory condition within the tumor microenvironment (TME). My research addresses both factors through two distinct directions:

Direction 1: Investigating the role of the tumor-intrinsic viral nucleic acid sensory pathway, RIG-I/MAVS. The roles of tumor-intrinsic viral nucleic acid sensing and its downstream type 1 IFN pathway remain underexplored and controversial, particularly regarding the RIG-I/MAVS pathway. It has been reported that MAVS expression is reduced across various cancer types, and MAVS-deficient mice exhibit increased susceptibility to chemically induced colorectal cancer (CRC). This suggests that the RIG-I/MAVS pathway and its downstream type 1 IFN signaling may play a critical role in cancer immunosurveillance. Using a CRC model, we demonstrated that the RIG-I/MAVS pathway and downstream type 1 IFN signaling are essential for modulating the tumor microenvironment, thereby enabling the suppression of colorectal cancer by CD8+ T cells.

Direction 2: Exploring the role of CD27 signaling in therapeutic cancer vaccination. While cancer vaccines have been in development for decades, optimizing their efficacy and durability—especially for established solid tumors—remains a challenge. Drawing on a study that revisited patients who survived 18 years after receiving a HER2+ breast cancer vaccine, we hypothesized that CD27 agonism would significantly enhance the efficacy of vaccine-induced antitumor immunity. Using human CD27 transgenic mice, we found that combining HER2 vaccination with anti-CD27 agonism enhanced HER2-specific responses, particularly within the long-lived CD4 memory T cell compartment. Murine models demonstrated approximately 40% tumor regression with the combined therapy, compared to only 6% with the vaccine alone. Depletion and adoptive transfer studies validated that CD4 T cells were essential for this therapeutic effect. These findings suggest that CD27 agonism enhances vaccine-induced, antigen-specific CD4 T cell responses, enabling durable antitumor immunity that is not entirely dependent on CD8 T cells.

Together, these findings underscore the necessity of addressing both local inflammatory defects and systemic T cell priming, establishing RIG-I/MAVS and CD27 as critical nodes in the design of next-generation immunotherapies.