Peiling Zhang

Abstract Background The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma (HCC) remains poor. Although serine‐ and arginine‐rich splicing factor (SRSF) family members play crucial roles in tumors, their impact on tumor immunology remains unclear. This study aimed to elucidate the role of SRSF10 in HCC immunotherapy. Methods To identify the key genes associated with immunotherapy resistance, we conducted single‐nuclear RNA sequencing, multiplex immunofluorescence, and The Cancer Genome Atlas and Gene Expression Omnibus database analyses. We investigated the biological functions of SRSF10 in immune evasion using in vitro co‐culture systems, flow cytometry, various tumor‐bearing mouse models, and patient‐derived organotypic tumor spheroids. Results SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8 + T cell activity. Mechanistically, SRSF10 interacted with the 3′‐untranslated region of MYB , enhancing MYB RNA stability, and subsequently upregulating key glycolysis‐related enzymes including glucose transporter 1 ( GLUT1 ), hexokinase 1 ( HK1 ), lactate dehydrogenase A ( LDHA ), resulting in elevated intracellular and extracellular lactate levels. Lactate accumulation induced histone lactylation, which further upregulated SRSF10 expression. Additionally, lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages, thereby activating transcription and enhancing pro‐tumor macrophage activity. M2 macrophages, in turn, inhibited the enrichment of CD8 + T cells and the proportion of interferon‐γ + CD8 + T cells in the tumor microenvironment (TME), thus creating an immunosuppressive TME. Clinically, SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1 (PD‐1) monoclonal antibodies (mAbs) in both murine and human preclinical models. Conclusions The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti‐PD‐1 resistance. Inhibiting SRSF10 by 1C8 may overcome anti‐PD‐1 tolerance in HCC.

// Yang Cao 1, * , Tao Zhu 1, * , Peiling Zhang 1 , Min Xiao 1 , Shuhua Yi 2 , Yan Yang 1 , Qinlu Li 1 , Shaoping Ling 3 , Yafei Wang 4 , Lili Gao 1 , Li Zhu 1 , Jue Wang 1 , Na Wang 1 , Liang Huang 1 , Peihong Zhang 2 , Qiongli Zhai 4 , Lugui Qiu 2 , Jianfeng Zhou 1, 2 1 Department of Hematology & Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, P.R. China 3 Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, P.R. China 4 Tianjin Cancer Hospital, Tianjin Medical University, Tianjin, P.R. China * These authors have contributed equally to this work Correspondence to: Jianfeng Zhou, email: jfzhou@tjh.tjmu.edu.cn Lugui Qiu, email: drqiu99@medmail.com.cn Keywords: TP53, CD58, mutation, copy number loss, DLBCL Received: September 24, 2015     Accepted: September 02, 2016     Published: November 4, 2016 ABSTRACT The advent of next generation sequencing (NGS) technologies has expedited the discovery of novel genetic lesions in DLBCL. The prognostic significance of these identified gene mutations is largely unknown. In this study, we performed NGS for the 27 genes most frequently implicated in 196 patients. Interestingly, TP53 mutations were found to be significantly more common in DLBCL with MYC translocations ( r = 0.446, P = 0.034). While no gene mutation was found to be more prevalent in patients with DLBCL with bone marrow involvement, MYD88 mutations were more common in primary DLBCL of the CNS or testis. To evaluate the prognostic significance of the abnormalities of these 27 genes, a total of 165 patients with newly diagnosed DLBCL, NOS were included in a multivariate survival analysis. Surprisingly, in addition to the TP53 mutation, CD58 mutation was found to predict poor clinical outcome. Furthermore, copy number loss of CD58 or TP53 was also identified to be an independent negative prognostic factor. Our results have uncovered the previously unknown critical impact of gene mutations on the prognosis of DLBCL and are fundamentally important for the future design of tailored therapy for improved clinical outcomes.

Abstract Noble metal materials are widely employed as benchmark electrocatalysts to achieve electrochemical water splitting which comprises of hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). However, the high cost and scarcity limit the wide ranging commercial applications of noble metal-based catalysts. Development of noble metal-free two dimensional (2D) carbon-based materials can not only reduce the consumption of noble metals, but also create materials with the characteristics of high active surface area, abundance, easy functionalization, and chemical stability, which may carve a way to promising electrochemical water splitting. In this review, noble metal-free 2D carbon-based electrocatalysts, including heteroatom (B, S, N, P, F, and O) doped graphene, 2D porous carbons modified with heteroatoms and/or transition metals, and 2D carbon-based hybrids are introduced as cost-effective alternatives to the noble metal-based electrocatalysts with comparable efficiencies to conduct HER, OER, and overall water splitting. This review emphasizes on current development in synthetic strategies and structure–property relationships of noble metal-free 2D carbon-based electrocatalysts, together with major challenges and perspectives of noble metal-free 2D carbon-based electrocatalysts for further electrochemical applications.