Increased T cell infiltration elicited by Erk5 deletion in a Pten-deficient mouse model of prostate carcinogenesis

Loveridge, C. J. et al. (2017) Increased T cell infiltration elicited by Erk5 deletion in a Pten-deficient mouse model of prostate carcinogenesis. Cancer Research, 77(12), pp. 3158-3168. (doi: 10.1158/0008-5472.CAN-16-2565) (PMID:28515147)

Abstract

Prostate cancer (PCa) 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 Erk5 can increase T cell infiltration in an established Pten-deficient mouse model of human PCa. Mice that were doubly mutant in prostate tissue for Pten and Erk5 (prostate DKO) exhibited a markedly increased median survival with reduced tumor size and proliferation compared to control Pten-mutant mice, the latter of which exhibited increased Erk5 mRNA expression. A comparative transcriptomic analysis revealed upregulation in prostate DKO mice of the chemokines Ccl5 and Cxcl10, 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ahmad, Professor Imran and Tan, Dr Ee and Galbraith, Ms Julie and Leung, Professor Hing and Blyth, Professor Karen and Welsh, Dr Michelle and Nixon, Mr Colin and Mui, Mr Ernest and Patel, Dr Rachana and Loveridge, Dr Carolyn and Sansom, Professor Owen
• Authors: Loveridge, C. J., Mui, E. J., Patel, R., Tan, E. H., Ahmad, I., Welsh, M., Galbraith, J., Hedley, A., Nixon, C., Blyth, K., Sansom, O., and Leung, H. Y.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 0008-5472
• ISSN (Online): 1538-7445
• Published Online: 17 May 2017