キタハラ　シユウジ   Kitahara Shiyuuji   北原　秀治    所属   医学研究科 医学研究科 (医学部医学科をご参照ください)    職種   特任准教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Inhibition of STAT3 Promotes Effector T Cell Infiltration But also Immunosuppression in the HCC Tumor Microenvironment
掲載誌名	正式名：Anticancer research 略　 称：Anticancer Res ISSNコード：17917530/02507005
掲載区分	国外
巻・号・頁	42(11),pp.5205-5215
著者・共著者	SASAKI Taketo†, SHIGETA Kohei*, KITAHARA Shuji, SUZUKI Yasuhiro, MATSUI Shimpei,, SEISHIMA Ryo, OKABAYASHI Koji, DUDA Dan G, KITAGAWA Yuko
発行年月	2022/11
概要	BACKGROUND/AIM:STAT3 is involved in the progression of several cancers, and has been proposed as target for therapy. Indeed, the multitargeted tyrosine kinase inhibitor drug regorafenib, which indirectly inhibits STAT3, can significantly enhance the effects of anti-programmed death receptor (PD)-1 therapy in hepatocellular carcinoma (HCC) models. Here, we studied the impact of a direct STAT3 inhibitor on the tumor microenvironment and PD-1 blockade efficacy in HCC models.MATERIALS AND METHODS:Orthotopic mouse models of HCC (RIL-175 and HCA-1 grafts in syngeneic mice) were used to test the efficacy of the selective STAT3 inhibitor STX-0119 alone or combined with anti-PD-1 antibodies. We evaluated the effects of therapy on tumor vasculature and the immune microenvironment using immunofluorescence (IF), cell viability assay and quantitative real-time (qRT)-PCR in tumor tissues.RESULTS:Combining anti-PD-1 antibodies with a STX-0119 failed to show a growth delay or survival benefit compared to each agent alone or control in any of the HCC models. Interestingly, evaluation of intratumoral CD8+ T cell infiltration by IF showed a significant increase after one-week treatment with STX-0119 (p=0.034). However, STX-0119 treatment simultaneously promoted increased immunosuppression in the tumor microenvironment by increasing the proportion of Tregs, tissue hypoxia and α-SMA activated cancer-associated fibroblasts (CAFs) measured by IF. Consistent with these findings, we found increased immature tumor vessels by IF and VEGF, Tgf-β and Vash2 expression by qPCR.CONCLUSION:Pharmacologic STAT3 inhibition could significantly enhance CD8+ T cell infiltration in HCC but also significantly alter the immunosuppression and vascular abnormalization in the tumor microenvironment.
DOI	10.21873/anticanres.16027
PMID	36288859