Latency-associated Peptide Identifies Immunoevasive Subtype Gastric Cancer With Poor Prognosis and Inferior Chemotherapeutic Responsiveness
Latency-associated Peptide Identifies Immunoevasive Subtype Gastric Cancer With Poor Prognosis and Inferior Chemotherapeutic Responsiveness
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潜伏相关肽可识别预后不良且化疗反应性较差的免疫逃避亚型胃癌
DOI：
10.1097/sla.0000000000003833
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发表时间：
2022-01-01
影响因子：
9
通讯作者：
Xu, Jiejie
中科院分区：
文献类型：
--
作者：
Cao, Yifan;He, Hongyong;Xu, Jiejie
补充数字内容可在文本目的：探讨胃癌的生存结局和化疗反应的预测的临床意义。背景：研究表明，在几种恶性肿瘤中，抗肿瘤药物具有重要的免疫调节作用。然而，其在胃癌中的作用和临床意义尚不清楚。研究方法：方法：收集复旦大学附属中山医院胃癌患者的五十六例肿瘤组织芯片标本、80例新鲜胃癌组织标本和328例胃癌患者的临床和转录组学资料。免疫组化、CIBERSORT和流式细胞术检测CD 45的表达和免疫结构。采用Kaplan-Meier曲线、考克斯模型和交互作用检验比较患者亚组的临床结局。结果如下：胃癌中高表达预示着较差的总生存率（P < 0.001，P < 0.001，P = 0.022）和对氟尿嘧啶辅助化疗较差的治疗反应性（相互作用P = 0.008）。CD 8 + T细胞浸润与免疫逃避性肿瘤微环境有关（P < 0.001）。LAP相关的功能障碍性CD 8 + T细胞具有耗竭表型，其效应分子如干扰素-γ、颗粒酶B和穿孔素减少，但程序性细胞死亡蛋白-1升高，这导致预后差和治疗反应性差。结论：本研究表明，胃癌特异性抗体能够识别免疫逃避亚型胃癌，提示胃癌特异性抗体可能是一个潜在的免疫学靶点，有助于指导胃癌患者个体化辅助治疗和随访计划。
Supplemental Digital Content is available in the text Objective: To examine the clinical significance of LAP to predict survival outcomes and chemotherapeutic responsiveness in gastric cancer. Background: LAP has been shown to possess significant immunoregulatory roles in several malignancies. However, the role and clinical significance of LAP in gastric cancer still remains unknown. Methods: Four hundred and fifty-six tumor tissue microarray specimens, 80 fresh tumor tissue samples of gastric cancer patients from Zhongshan Hospital, Fudan University and transcriptomic and clinical data of 328 gastric cancer patients from the Cancer Genome Atlas were analyzed. LAP expression and immune contexture were examined by immunohistochemistry, CIBERSORT, and flow cytometry. Clinical outcomes of patient subgroups were compared by Kaplan-Meier curves, Cox model and interaction test. Results: High LAP expression predicted poor overall survival (P < 0.001, P < 0.001, and P = 0.022) and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy (P = 0.008 for interaction) in gastric cancer. LAP was associated with immunoevasive tumor microenvironment featured by dysfunctional CD8+ T cells infiltration (P < 0.001). The LAP-associated dysfunctional CD8+ T cells had an exhausted phenotype with decreased effector molecules such as interferon-γ, granzyme B, and perforin, but also elevated programmed cell death protein-1, which resulted in poor prognosis and inferior therapeutic responsiveness. Conclusions: This study revealed that LAP could identify immunoevasive subtype gastric cancer, indicating LAP might be a potential immunotherapeutic target and facilitate patient counseling on individualized adjuvant therapy and follow-up scheduling in gastric cancer.