Coactivation of innate immune suppressive cells induces acquired resistance against combined TLR agonism and PD-1 blockade

T cell responses, in multiple animal models. The failure was attributed to the coactivation of innate suppressive cells, such as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) expressing CXCR2, through high CXCL1 production by macrophages in the TME upon OK-432 treatment. A triple combination treatment with OK-432, PD-1 blockade, and a CXCR2 neutralizing antibody overcame the resistance induced by PMN-MDSCs, resulting in a stronger antitumor effect than that of any dual combinations or single treatments. The accumulation of PMN-MDSCs was similarly observed in the pleural effusions of patients with lung cancer after OK-432 administration. We propose that successful combination cancer immunotherapy intended to stimulate innate antitumor immunity requires modulation of unwanted activation of innate immune suppressive cells, including PMN-MDSCs.