Evaluation of the Combination Therapy for Cancers of Traditional Radiotherapy and Immunotherapy with Tlr2 Blockade and Its Therapeutic Mechanism Study

The disruption of the immunosuppression within tumor microenvironments by recent immunotherapies with immune checkpoint blockades, leads to encouraging therapeutic effects and controllable adverse events in oncology. However, several treatment-limiting mechanisms appear to be very disappointed, particularly in those tumors lacking the infiltration immune cells. Interestingly, recent evidence in tumor models and patients shows that irradiation can trigger immune-based therapeutic responses. The response is related to the well-known abscopal effect, a phenomenon in the treatment of metastatic cancer where localized irradiation of a tumor shrinks both the irradiated tumor as well as a metastasis far from the irradiated area. Such effects are attributed to the up-regulation of tumor specific immune responses, including IFN-γ. TLR expression within the tumor microenvironment appears to promote cell proliferation, metastasis, or angiogenesis in cancers. Also, TLR2 signaling is known to contribute to the differentiation of Th17 cells and production of IL-17. It indicates TLR2 signaling within the tumor microenvironment inhibiting anti-tumor immunity. Indeed, our recent results showed that the absence of TLR2 reduced the tumor growth and induced anti-tumor immunity by increasing the production of IFN-γ and decreasing the level of IL-17. Supplement of anti-TLR2 yielded the increased interferon (IFN)-γ and reduced IL-10 and IL-17 responses. It leads the hypothesis that targeting TLR2 signaling is able to treat tumor through modulating the immunosuppressive responses, such as Th17 or T regulatory cells (Treg). Indeed, the preliminary results from the combined traditional radiotherapy and cancer immunotherapy, which we have been working since Aug 2019, demonstrated the significant improved therapeutic efficacy than that of the conventional radiotherapy or immunotherapy only. Therefore, here we intend to continue our study and establish the therapeutic platform of the combined traditional radiotherapy and cancer immunotherapy with anti-TLR2 blockade. Also, the underline mechanisms will be investigated by utilizing the gene engineered and deficient animals as well as adoptive cell transfer experiments. Since large research effort is necessary to understand the therapeutic mechanisms and then optimize the therapeutic strategy, so the results obtained in this project will provide us the translational evidence of whether immunotherapy is optimally combined with radiation therapy and directly benefit the future clinical applications.

Project ID:PC10907-1309
External Project ID:MOST109-2320-B182-037