Presentation Authors: Haoran Liu, Libin Yan, Kun Tang, Tao Ye, Xifeng Sun, Xiaoqi Yang, Hua Xu, Peng Yuan*, Wuhan, China, People's Republic of
Introduction: Immune checkpoint blockade of the inhibitory immune receptors PD-L1, and PD-1 has emerged as a successful treatment strategy for several advanced cancers. Here we demonstrate that SETD2-miR-339 regulates the PD-L1/PD-1 pathways in renal cell cancer.
Methods: Gene expression and correlation were examined by high throughput RNA-Seq. Potential miRNA regulated by SETD2 was examined by miRNA-assay. Chromatin immunoprecipitation was performed to determine whether SETD2 directly activated the miRNA promoter. Luciferase assay was performed to verify the precise target of miRNA. Vivo optical bioluminescence imaging represent subcutaneous tumor progression in BABL/C mice.
Results: Low levels of SETD2 and miR-339 in tumor are negatively correlated with PD-L1 and the progression-free survival of RCC patients. Co-culturing T cells with SETD2 transfected OSRC-2 cells, we found that SETD2 could influence PD-L1 associated T-cell regulator cytokines and apoptosis. Mechanistic investigations demonstrated that SETD2 directly targeting miR-339 promoter, while miR-339 inhibited PD-L1 through direct binding to the 3â€™-UTR. Restoration of SETD2 and miR-339 expression reverses T cell liveness, which is accompanied by blockage of the PD-L1 immune checkpoint. The synergistic effect of immunotherapy is associated with the proliferation of functional cytotoxic CD8+ T cells and the inhibition of myeloid-derived suppressive cells and regulatory T cells which influence the subcutaneous tumor progression in BABL/C mice.
Conclusions: Collectively, our data suggest a biological and functional interaction between PD-L1 and T cell through histone methyltransferaseÂ and microRNA regulatory cascade. SETD2 inhibit RCC progression by blocking the PD-L1 immune checkpoint and activating PD-L1 dependent CTLS and reduction regulatory cytokine through a newly identified SETD2-miR-339-PD-L1 pathway in vivo and in vitro.
Source of Funding: This project was supported by the National Natural Science Foundation of China (81370805, 81470935, 81500534, 81602236, 81670645)