Targeting Depletion of Myeloid-Derived Suppressor Cells Enhances PD-L1 Blockade Efficacy in Gastric Cancer

Abstract Background Gastric cancer (GC) remains one of the most common malignancieswith poor prognosis worldwide. Immunotherapy based on PD-1/PD-L1 immune checkpoints has achieved robust and durable responses in various types of cancer, but only a subset of gastric cancer patients benefits from it.Myeloid-derived suppressor cells (MDSCs) have been demonstrated to suppress antitumor immunityand induceresistanceto PD-1/PD-L1 blockade immunotherapy. Death receptor5 (DR5), a receptor of TNF-related apoptosis-inducing ligand(TRAIL), is upregulated in MDSCs and is also commonly expressed on cancer cells, making it a desirable target for both MDSCs and DR5-positive GC. In this study, we evaluated the MDSCs depleting and immune modulating effect of the agonist DR5 antibody (MD5-1), and tested the therapeutic effectof targeting DR5 in combination with anti-PD-L1 as a new strategyfor the treatment of GC. Methods The MDSCs and their DR5 expression insyngeneic GC murine model were evaluated. TheMDSCs depleting effect by MD5-1 wereinvestigated. We compared the antitumor efficacy of MD5-1 in GC bearing T cell-deficient nude mice andsyngeneic 615 mice, and assessed its immune correlates. The antitumor effect of MD5-1 combininganti-PD-L1 in syngeneic GC murine model were tested, the tumor growth, mice survival and intratumoral T cell infiltration and activation were evaluated. Results The MDSCs accumulate in the gastric tumor-bearing 615 mice express high levels of DR5. Targeting DR5 using MD5-1specifically depleted MDSCs and enhancedT cell antitumor response, resulted in tumor growth inhibition.MD5-1 enhanced the antitumor effect of anti-PD-L1 antibody, led to complete regression in 40% ofestablished tumors and significantly extended the survival tumor-bearing mice. The enhanced antitumor effect by MD5-1 combining anti-PD-L1 was associatedwith increased CD8+ T cell infiltration and activation. Conclusions These results show that targeting DR5 enhances the antitumor effect of PD-L1 blockadetherapy in gastric cancer through eliminating MDSCs and improving CD8+T cell antitumor response.Thus, targeting DR5 in combination with anti-PD-L1 may be a novel immunotherapy strategy forgastric cancer.