Postdoctoral Fellow Northwestern Feinberg School of Medicine Chicago, Illinois, United States
Abstract Text: Patients with metastatic castration resistant prostate cancer (mCRPC) have poor prognosis and overall survival (OS). Although immunotherapies such as anti-PD-1/L1 checkpoint blockade have produced significant tumor regressions in melanoma and lung cancer, treatment efficacy is significantly impaired in prostate cancer tumors. High expression of NKG2D receptor agonists MICA/B is associated with poor prognosis in human carcinomas. Soluble MIC (sMIC) shed by tumor cells suppresses CD8 T cell activation and accelerates tumor progression. In “humanized” TRAMP/MICB mice, sMIC-neutralizing anti-MIC mAb (B10G5) causes regression of prostate tumors by 1) sequestering sMIC, and 2) stabilizing/sustaining NKG2D and CD3ζ signaling and CD28 expression, re-invigorating CD8 T cell anti-tumor responses. NKG2D signaling modifies expression of epigenetic factors, and is essential in certifying CD8 T cell stemness necessary for tumor control. In this preliminary study, we used scRNA-seq of CD8 TILs from TRAMP/MICB mice treated or untreated with B10G5 to investigate the hypothesis that B10G5 differentially reprograms CD8 T cells at the genetic and epigenetic level via sustained NKG2D pathway co-stimulation, thereby optimizing TCR-dependent effector and memory responses. We found that B10G5-treated mouse tumors were enriched in central memory CD8 TILs expressing high levels of NKG2D and TCF7, as well as GZMKhi PD-1+ CD8 TILs upregulating epigenetic modifiers associated with H3K4 methylation and H3K27 demethylation and maintaining homeostasis of activated CD8 T cells, such as KMT2A/E, EZH2, and CREBBP. These results establish a groundwork for identifying targets for epigenetic alteration via NKG2D co-stimulation of CD8 TILs within the prostate tumor microenvironment.
