ABSTRACT
@#[Abstract] Metabolic reprogramming is one of the characteristics of tumors and an important potential target for tumor therapy. The effect of the interaction between tumor and immune cells on metabolic reprogramming is one of the key factors determining the anti-tumor immune response. Tumor metabolism not only plays a key role in maintaining tumor genesis and survival, but also affects immune cells by releasing metabolites such as arginine and PGE2, thereby affecting the tumor immune microenvironment. The interaction between tumor cells and immune cells leads to metabolic competition in the tumor immune microenvironment, which limits the normal metabolism of nutrients and forms an acidic environment, and ultimately leads to a weakened anti-tumor immune response and the formation of an immunosuppressive microenvironment. Moreover, there are alterations in metabolism of immune cells during the process of immune responses, that is metabolic reprogramming occurs in immune cells during their proliferation, differentiation and performance of cellular functions. Therefore, understanding the regulatory mechanism of metabolic reprogramming of tumor cells and immune cells in tumor immune microenvironment will enable researchers to find therapeutic means of targeting metabolic pathways in anti-tumor immunotherapy.
ABSTRACT
@#免疫治疗是继传统的手术、化疗、放疗和靶向治疗后的一种新兴的肿瘤治疗手段。以免疫检查点抑制剂（ICP）疗法为 代表的免疫治疗在肿瘤临床治疗中取得了突破性进展。随着ICP在临床的应用，用于肿瘤诊断、疗效及预后的生物标志物的探 索也成为肿瘤免疫治疗研究的热点。在当前精准医疗的背景下，多项临床研究证实程序性死亡蛋白配体-1（PD-L1）表达、肿瘤突 变负荷、微卫星不稳定以及肿瘤微环境相关的生物标志物与免疫治疗的疗效密切相关。然而，许多患者并不能从这些疗法中受 益，缺乏有效的疗效和预后生物标志物在很大程度上限制了其临床应用。本文总结了有关免疫治疗生物标志物的相关研究文 献，重点关注免疫治疗疗效和预后生物标志物在临床应用的相关研究进展，阐述可能有助于指导临床决策及治疗方案选择的潜 在生物标志物。
ABSTRACT
@# Objective: To investigate the immunosuppressive effect and underlying molecular mechanisms of Myeloid-derived suppressor cells (MDSCs) on T cells activity through IL-6activatingSTAT3/IDO signaling pathway. Methods: Twenty pairs of cancer tissues and the corresponding adjacent normal tissues from breast cancer patients treated at Tianjin Medical University Cancer Institute and Hospital from November 2015 to February 2016 were collected for this study; in the meanwhile, peripheral blood samples from 40 healthy donorswere also collected. CD33+ cells in tumor tissues and CD33+ CD14 + cells in peripheral blood of helthy donors were sorted out with MicroBeads technology. CD33+ cells were in vitro co-cultured with breast cancer cell line MDA-MB-231 to induce MDSCs. Flow cytometry was used to detect the proportion of CD45+ CD13+CD33+CD14-CD15- MDSCs.Western Blotting was used to detect the expression ofSOCS1，SOCS3, JAK1, JAK2, TYK2, STAT1, STAT3 and their phosphorylation levels. qRT-PCR was used to detect the expression of IL-6 and SOCS1-3. CCK8 was used to detect the T cell proliferation. Annexin V staining was used to detect T cell apoptosis. ELISA was used to detect IL-10 and IFN-γ secreted by T cells. Results: There were MDSCs infiltration in all 20 cases of breast cancer tissues for different levels (15.3%~58.1%), with a mean level of (29.82± 11.46%); the infiltration of IL-6high group was significantly higher than that of the IL-6low group [（13.75±3.44） % vs（4.31±1.50） %， P< 0.05], indicating that IL-6 expression was positively correlated with MDSCs infiltration (R2=0.4399, P<0.01). In vitro experiments showed that tumor-derived IL-6 significantly promoted the generation and immunosuppressive activity of MDSCs (P<0.05), which could be reversed by the blocking of IL-6. In the meanwhile, the expression of SOCS3 in MDSCs that induced in vitro was absent, which can be inhibited by blocking IL-6 (P<0.05). Conclusion: The study has demonstrated that tumor-derived IL-6 stimulates the continuous activation of the JAK/STAT signaling pathway and the absence of SOCS3 expression in MDSCs, thereby promoting the infiltration, generation and immunological activity of MDSCs. Therefore, IL-6 signaling pathway can be used as therapeutic target to weaken MDSCs generation and reverse MDSCs activity.
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Objective:To investigate the function of breast cancer susceptibility gene variants in predicting breast cancer risk and guid-ing clinical treatment through DNA sequencing. Methods:This study involved 146 patients, 71 high-risk cases, and 55 healthy people, totaling 272 cases. The subjects were treated in Tianjin Medical University Cancer Institute and Hospital from November 2013 to July 2015. Genomic DNA was sequenced by a second generation sequencing platform. All exon areas of six common breast cancer suscepti-bility genes (BRCA1, BRCA2, PTEN, STK11, TP53, and RAP1) were sequenced through amplicon sequencing method. Meaningful vari-ants including single nucleotide variants (SNVs), insertion-deletions (InDels) and nonsense mutations were selected and statistical methods, such as t test andχ2 test, were used to analyze the statistical differences in incidence rates among three groups. Results:A total of 177 meaningful variants were confirmed, including 50 SNVs, 8 nonsense mutations, and 9 InDels. Among the variants, 31 were recorded in the Exome Aggregation Consortium (ExAC), 40 were noted in ClinVar database, and 21 were not encoded in the present da-tabase, which were defined as new variants in this study. Conversely, 57 variants (85.1%) were found in breast cancer patients and high-risk cases, and the incidence of axillary lymph node metastasis (P=0.010) and pathological stages (P=0.002) in mutation positive patients were both higher than mutation negative patients. Moreover, the percentage of family history of cancer (P=0.005) and triple negative breast cancer (P=0.009) were both higher in patients carrying pathogenic mutations than in nonpathogenic patients. Conclu-sion:Breast cancer susceptibility gene variants may not only be a tool used to predict the risk of getting breast cancer but also a mean-ingful guideline for the clinical treatment and prognosis evaluation.