PAK4 inhibition improves PD1 blockade immunotherapy in prostate cancer by increasing immune infiltration.

ABSTRACT

Antitumor immunity requires lymphocytes to localize to the tumor. Prostate cancers (PCs) are immunologically cold and tend to lack T-cell infiltration. Most advanced PCs are insensitive to PD1 blockade therapies. Using syngeneic RM1 prostate tumors, p21-activated kinase-4 (PAK4) knockdown (KD) and pharmacological inhibition was assessed in C57BL/6J mice treated with PD1 antibodies (αPD1). RNASeq was used to characterize the immune response in the tumor. Immunohistochemistry, flow cytometry, and in vivo blocking studies confirmed the role of cell surface proteins in the generation of immune responses. In The Cancer Genome Atlas, PAK4 expression was inversely correlated with immune cell infiltration. PAK4 expression was controlled by the androgen receptor and its pioneering factor, FOXA1. PAK4 KD increased CD8+ T-cell infiltration and expression of IFNγ response genes. PAK4 KD also upregulated angiogenesis and endothelial cell adhesion molecules in the tumor microenvironment, contributing to CD8+ lymphocyte recruitment. Pharmacological inhibition of PAK4 made PC more responsive to immunotherapy with αPD1. A decrease in PAK4 activity increases immune activation and vascularity, which increases CD8+ lymphocyte infiltration into the tumor. Therefore, targeting PAK4 may improve the response of human PC to immunotherapy.