Increased T-cell Infiltration Elicited by <i>Erk5</i> Deletion in a <i>Pten</i>-Deficient Mouse Model of Prostate Carcinogenesis.

Abstract

Prostate cancer does not appear to respond to immune checkpoint therapies where T-cell infiltration may be a key limiting factor. Here, we report evidence that ablating the growth regulatory kinase <i>Erk5</i> can increase T-cell infiltration in an established <i>Pten</i>-deficient mouse model of human prostate cancer. Mice that were doubly mutant in prostate tissue for <i>Pten</i> and <i>Erk5</i> (prostate DKO) exhibited a markedly increased median survival with reduced tumor size and proliferation compared with control <i>Pten</i>-mutant mice, the latter of which exhibited increased <i>Erk5</i> mRNA expression. A comparative transcriptomic analysis revealed upregulation in prostate DKO mice of the chemokines <i>Ccl5</i> and <i>Cxcl10</i>, two potent chemoattractants for T lymphocytes. Consistent with this effect, we observed a relative increase in a predominantly CD4⁺ T-cell infiltrate in the prostate epithelial and stroma of tumors from DKO mice. Collectively, our results offer a preclinical proof of concept for ERK5 as a target to enhance T-cell infiltrates in prostate cancer, with possible implications for leveraging immune therapy in this disease. <i>Cancer Res; 77(12); 3158-68. ©2017 AACR</i>.