The regulation of the host immune response to prostate cancer mediated by X-ray and by PRMT5 phosphorylation (Radiation Medicine and Markey Cancer Center Collaborative Bench to Bedside pilot) (RPA Pilot / Seed Project)

"Radiation treatment of tumors is expected to stimulate the host immune system against cancer, as damaged tumor tissues sputter neoantigens. However, the prostate cancer is known with its low immune response, and
immune checkpoint blockage protocols such as PD1/PD-L1 inhibition has not seen a significant success. Additional strategies to break the immunologically ‘cold’ prostate cancer are highly anticipated.Protein arginine methyltransferase 5 (PRMT5) is a critical epigenetic factor that methylates arginine (R) side chains of cellular proteins including histones. High PRMT5 expression has been associated with poor prognosis of prostate cancer patients. Through its epigenetic gene regulatory function, PRMT5 activates DNA doublestrand break repair to confer radio-resistance of the cancer cells. Another role of PRMT5 in radiation resistance of cancer is to suppress the host immune system. However, the molecular mechanism of PRMT5-mediated immune evasion remains largely unknown. We have found that PRMT5 is phosphorylated by polo-like kinase 1 (PLK1). Our further investigation suggests that phosphorylation of PRMT5 by PLK1 significantly alters gene regulation network in the affected cells, including suppression of CD40. CD40 is essential for antigen presenting cells for T cell maturation to target tumor cells. We hypothesize that down-modulation of CD40 in the tumor microenvironment by PRMT5 is a significant contributor of the immune suppression in the prostate cancer. To elucidate this hypothesis, we have successfully generated a genetically engineered mice (GEM) that harbor S470D PRMT5, the mimicry of PLK1-phosphorylated PRMT5. Using this refined GEM model, we propose to test the role of PRMT5 modulation
by PLK1 on the host immune activation against TRAMP-C2 allograft tumors after X-ray irradiation. This pilot project will strengthen our R01 grant proposal to be submitted near future. Through this project, we will establish the workflow of spatially fractionated radiation for mice, taking the full advantage of the small
animal radiation research (SARRP) platform at UK’s X-ray Service Core, to focus on the immune responses against radiated tumor tissues."