Targeting depletion of myeloid-derived suppressor cells potentiates PD-L1 blockade efficacy in gastric and colon cancers

Abstract

ABSTRACT Myeloid-derived suppressor cells (MDSCs) have been demonstrated to suppress antitumor immunity and induce resistance to PD-1/PD-L1 blockade immunotherapy in gastric and colon cancer patients. Herein, we found that MDSCs accumulate in mice bearing syngeneic gastric cancer and colon cancer. Death receptor 5 (DR5), a receptor of TNF-related apoptosis-inducing ligand (TRAIL), was highly expressed on MDSCs and cancer cells; targeting DR5 using agonistic anti-DR5 antibody (MD5-1) specifically depleted MDSCs and induced enrichment of CD8+ T lymphocytes in tumors and exhibited stronger tumor inhibition efficacy in immune-competent mice than in T-cell-deficient nude mice. Importantly, the combination of MD5-1 and anti-PD-L1 antibody showed synergistic antitumor effects in gastric and colon tumor-bearing mice, resulting in significantly suppressed tumor growth and extended mice survival, whereas single-agent treatment had limited effect. Moreover, the combination therapy induced sustained memory immunity in mice that exhibited complete tumor regression. The enhanced antitumor effect was associated with increased intratumoral CD8+ T-cell infiltration and activation, and a more vigorous tumor-inhibiting microenvironment. In summary, our findings highlight the therapeutic potential of combining PD-L1 blockade therapy with agonistic anti-DR5 antibody that targets MDSCs in gastric and colon cancers.