Inhibition of SHP-1 /2 blocks antigen cross-presentation by human macrophages and dendritic cells

PD-1 immune checkpoint therapy aims to stimulate T-cell responses against cancer, but faces challenges due to resistance, rendering it ineffective for a significant subset of patients. Inhibitors of SHP-1 and SHP-2, widely expressed protein tyrosine phosphatases known for their pro-cancer and immunosuppressive properties, have attracted attention for their potential to enhance therapy efficacy and overcome resistance when combined with immune checkpoint PD-1 blockade. However, how SHP-1/2 inhibition affects antigen presenting cells is incompletely understood. In this study, we evaluated the effect of SHP-1/2 inhibition on antigen cross-presentation by human monocyte-derived macrophages and dendritic cells, using T cell reporter cell lines specific for epitopes derived from cancer antigens NY-ESO-1 and gp100. Our findings indicate that SHP-1/2 inhibitor NSC-87877 significantly reduces the cross-presentation efficiency of both antigens. Mechanistically, we show that SHP-1/2 inhibition blocks endo/lysosomal acidification and the activation of cathepsin proteases. The reduction of antigen cross-presentation upon SHP-1/2 inhibition potentially limits the effectiveness of the combination therapy with immune checkpoint inhibition.