CD8+T细胞耗竭发生和特征及其与肿瘤免疫治疗耐药的研究进展

免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)是治疗多种肿瘤的重要手段,但耐药成为其最大难题。肿瘤免疫治疗耐药与肿瘤微环境(tumor microenvironment,TME)密切相关,TME中CD8⁺T细胞耗竭不仅持续性高表达抑制性受体(inhibitory receptors,IRs),同时也是导致ICIs耐药的关键环节,靶向IRs为克服免疫治疗耐药提供了新思路。本文将重点对CD8⁺T细胞耗竭发生和特征及其与肿瘤免疫治疗耐药性相关的研究进行综述。     

碳离子（12C6+）抑制JAK2/STAT3通路促进肺癌中CD8+ T细胞浸润的研究

目的 探索碳离子（¹²C⁶⁺）照射后JAK2/STAT3通路的改变及下游蛋白FOXP3调控的肺癌中CD8⁺T细胞的浸润差异。方法 基于C57BL/6小鼠Lewis荷瘤模型的RNA测序分析,筛选出碳离子照射后肺癌中显著改变的JAK2/STAT3通路及相关的差异表达基因及蛋白如FOXP3。利用R软件“GSVA”中ssGSEA免疫浸润算法,探索FOXP3与肺癌免疫微环境中主要免疫细胞浸润的相关性并基于碳离子联合STAT3抑制途径（氯硝柳胺）对肺癌中CD8⁺T细胞浸润进行分析。结果 碳离子照射后,肺癌中JAK2/STAT3通路被抑制,相关基因和蛋白表达下调。基于ssGSEA算法的免疫评分显示,FOXP3表达与肺癌免疫微环境中CD8⁺T细胞浸润呈显著负相关。通过碳离子照射联合STAT3抑制剂氯硝柳胺,进一步明确了靶向JAK2/STAT3通路对于增加肺癌中CD8⁺T细胞浸润的协同作用。结论 碳离子（¹²C⁶⁺）可以通过靶向JAK2/STAT3通路与免疫治疗发挥协同增效的作用。     

干细胞样CD8+T细胞在抗肿瘤免疫治疗中的地位与演进效应

以抗细胞程序性死亡-1/细胞程序性死亡-配体1(programmed cell death-1/programmed cell death-ligand 1,PD-1/PD-L1)为代表的免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)治疗显现了CD8⁺T细胞在治疗和可能治愈恶性肿瘤方面的潜力。但仅约20%的患者对ICIs治疗获益,因此阐明CD8⁺T细胞在免疫微环境中的有效抗肿瘤功能,及其分子和空间的决定因素尤为重要。具有自我更新、增殖分化和杀伤肿瘤细胞能力的干细胞样CD8⁺T细胞亚群,在介导抗肿瘤免疫效应方面扮演极为重要的角色。本文就干细胞样CD8⁺T细胞在抗肿瘤免疫循环中的地位与演进效应进行综述。     

基于质谱流式细胞技术揭示TP53突变型乙型肝炎病毒相关性肝细胞癌的免疫微环境特征

目的 探讨TP53突变型乙型肝炎病毒（hepatitis B virus，HBV）相关性肝细胞癌（hepatocellular carcinoma，HCC）的肿瘤免疫微环境特征。方法 收集2018—2019年广西医科大学附属肿瘤医院肝胆外科手术切除的38例HCC患者活体组织标本及其配对癌旁组织标本，提取组织DNA，并进行基因突变分析。采用质谱流式细胞术（CyTOF）比较TP53突变组和TP53未突变组中癌组织与癌旁组织以及两组癌组织之间的免疫微环境特点。结果 采用CyTOF鉴定TP53突变组和TP53未突变组所有免疫细胞，结果鉴定为22个细胞亚群，包括CD4⁺T细胞亚群、CD8⁺T细胞亚群、B细胞亚群、树突细胞亚群、自然杀伤（natural killer cell，NK）细胞亚群、NKT细胞亚群、粒细胞亚群和2个未知细胞亚群。其中，TP53突变组癌组织中CD8⁺T细胞和CD4⁺T细胞的表达比例均较未突变组癌组织高（2.26% vs 0.47%，P=0.028；7.53% vs 3.55%，P=0.046）。结论 TP53突变型HBV相关性HCC的肿瘤免疫微环境具有免疫异质性。     

CD4+/CD8+ T淋巴细胞在肝细胞癌组织中的浸润及与预后的相关性研究

目的 检测CD4⁺/CD8⁺ T淋巴细胞在肝细胞癌（hepatocellular carcinoma,HCC）组织中的浸润程度,并分析其与预后的相关性。方法 收集行肝切除术的HCC患者215例,采用免疫组化技术检测CD4⁺/CD8⁺ T淋巴细胞在HCC癌组织中的浸润程度,根据浸润情况比较患者肝切除术后无瘤生存率和总生存率。结果 CD4⁺ T淋巴细胞高浸润和低浸润比例分别为60.9%和39.1%。CD4⁺ T淋巴细胞高浸润组患者总生存率和无瘤生存率均显著高于低浸润组（P=0.015,P=0.038）。CD8⁺ T淋巴细胞高浸润和低浸润比例分别为34.9%和65.1%。CD8⁺ T淋巴细胞高浸润组患者的总生存率和无瘤生存率亦显著高于低浸润组患者（P=0.033,P=0.047）。结论 CD4⁺或CD8⁺ T淋巴细胞低浸润可能与HCC患者术后不良预后相关。     

基于生物信息学分析细胞周期蛋白依赖蛋白激酶5表达与胃癌免疫浸润细胞的相关性

目的探讨细胞周期蛋白依赖蛋白激酶5(CDK5)表达与胃癌免疫浸润细胞的关系。方法采用基因富集分析(GSEA)及单样本基因富集分析(ssGSEA)对免疫相关基因集进行富集评分,采用CIBERSORT网站对免疫细胞组分进行评分。收集36例行胃癌根治术的患者的胃癌组织,采用免疫组织化学法检测CDK5及CD8表达水平。结果胃癌组织中CD8⁺T淋巴细胞及记忆B淋巴细胞浸润数目均明显少于癌旁组织。CDK5高表达患者具有更高的免疫基因富集评分(尤其是周围炎症基因集与抗原呈递细胞共刺激基因集)。CDK5表达与免疫相关基因呈正相关,而与免疫浸润细胞呈负相关。CDK5及CD274高表达患者均有更高的总生存率(OS)。免疫组织化学结果显示,CDK5高表达组患者CD8⁺T淋巴细胞浸润数目明显多于CDK5低表达组(P﹤0.01)。结论胃癌中CDK5表达与CD274表达及CD8⁺T淋巴细胞浸润相关,可能参与胃癌免疫逃逸。     

结直肠癌及腺瘤患者CD4+、CD8+和CD28+T淋巴细胞的亚群变化及临床意义

背景与目的：结直肠癌（colorectal cancer,CRC）严重影响患者生存。探讨肿瘤微环境（tumor microenvironment,TME）T细胞亚群在CRC和腺瘤中的表达及意义。方法：用免疫组织化学法和流式细胞术对51例健康人（对照组）、46例结直肠腺瘤（腺瘤组）、100例CRC（癌症组）和15例CRC术后（癌术后组）患者进行T细胞亚群检测。结果：① 对照组、腺瘤组及癌症组3组中CD4⁺T细胞的阳性率分别是90.00%、43.75%及32.65%,CD8⁺T淋巴细胞的阳性率分别是30.00%、56.25%及75.51%,CD28⁺T淋巴细胞的阳性率分别是42.86%、30.00%及20.00%。② 对照组、腺瘤组及癌症组3组中CD4⁺、CD4⁺/CD8⁺、CD28⁺、CD8⁺CD28⁺和CD8^－CD28⁺逐渐降低,CD8⁺、CD8⁺CD28^－逐渐增加（P＜0.05）;癌术前术后T细胞亚群差异有统计学意义（P＜0.05）。结论：① CRC微环境T细胞亚群中CD4⁺、CD4⁺/CD8⁺、CD28⁺、CD8⁺CD28⁺和CD8^－CD28⁺呈递减趋势,CD8⁺、CD8⁺CD28^－呈递增趋势,且在癌前病变腺瘤中已逐步出现上述趋势变化。② CRC患者行肿瘤切除术后,其T细胞亚群有所恢复,故在一定程度上,CRC中T细胞亚群的变化可以早期预测结直肠疾病的发展。     

PD-1抑制剂治疗胃癌致白癜风样色素脱失1例并文献复习

<正>随着免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的应用,许多免疫相关不良事件(immune-related adverse effects,irAEs)的发生率也随之上升。其中皮肤不良事件是免疫检查点抑制剂治疗过程中最常见的不良事件,包括皮疹、瘙痒和白癜风样色素脱失^[1]。白癜风样色素脱失是接受免疫治疗的恶性黑色素瘤患者的一种特征性皮肤不良事件,通常提示恶性黑色素瘤患者可能从PD-1抑制剂中获益^[2],其在非恶性黑色素瘤患者中罕见。本文介绍了1例胃癌患者接受免疫治疗后出现白癜风样色素脱失病例并对既往文献进行回顾。     

肿瘤组织T细胞亚群对结直肠癌患者术后疾病进展风险的预测价值

目的 探讨肿瘤组织T细胞亚群对结直肠癌患者术后疾病进展风险的预测价值。方法 选取2018年12月至2020年6月我院收治的102例结直肠癌手术患者为研究对象，患者术后接受辅助治疗6个月，收集患者入院时的临床资料，采用免疫组织化学方法检测患者术后CD4⁺T细胞、CD8⁺T细胞、CD4⁺/CD8⁺和Foxp3⁺Tregs表达状况。对患者辅助化疗后随访观察1年，根据是否出现疾病进展分为进展组和非进展组，通过多因素Logistic回归分析探讨结直肠癌患者术后疾病进展风险的影响因素。结果 截止2022年1月1日，99例获得随访，其中41例(41.41%)疾病进展归为进展组，58例(58.59%)未发生疾病进展归为非进展组。两组CD4⁺T细胞、CD8⁺T细胞、CD4⁺/CD8⁺及Foxp3⁺Tregs细胞水平比较，差异均有统计学意义(P<0.05)。多因素Logistic回归...     

三焦针灸法对中晚期胃腺癌癌因性疲乏的疗效及对免疫功能的影响

目的 观察三焦针灸法治疗中晚期胃腺癌癌因性疲乏的疗效及对免疫功能的影响。方法 收集2019年1月至2020年12月天津中医药大学第一附属医院收治的中晚期胃腺癌癌因性疲乏患者200例。应用随机数字表法将患者分为对照组和治疗组各100例；剔除脱落患者后，对照组85例，治疗组77例。对照组接受常规中西医对症治疗，治疗组在此基础上联合三焦针灸法治疗。观察两组治疗前后的卡氏功能状态(Karnofsky performance status,KPS)评分、Piper量表评分、红细胞计数、血红蛋白浓度以及淋巴细胞亚群(CD3⁺T细胞、CD4⁺T细胞、CD8⁺T细胞、NK细胞和B细胞)百分比和绝对计数的变化。结果 对照组治疗后KPS评分升高且Piper量表中行为维度评分、红细胞计数、血红蛋白浓度和淋巴细胞亚群CD4⁺T细胞绝对计数均下降，差异均具有统计学意义(均P<0.05)。对照组治疗前后Piper量表中情绪维度、感觉维度、认知维度和总分评分以及淋巴细胞亚群百分比、CD3⁺T细胞绝对计...     

胆固醇代谢调控CD8+T细胞抗肿瘤作用的研究进展

CD8+T细胞又名细胞毒性T淋巴细胞(cytotoxic T lymphocyte,CTL),具有直接杀死病原体感染细胞和癌细胞的作用.然而,CD8+T细胞常常丧失其效应功能,继而限制肿瘤微环境中的抗肿瘤免疫,因此,如何重新激活CD8+T细胞的抗肿瘤效力是目前需要解决的问题.最近研究发现,胆固醇代谢在肿瘤中发挥重要作用...     

Nutrition deprivation affects the cytotoxic effect of CD8 T cells in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the third leading cause of cancer-related death worldwide. Factors including carcinogens, infection of hepatitis viruses, alcohol abuse, and metabolic disorders such as non-alcoholic fatty liver disease mainly contribute to HCC initiation and progression. Immunotherapy is one of the most powerful tools for unresectable HCC treatment in patients. CD8⁺ T cells are a major immune component in the tumor microenvironment with cytotoxic effects against cancer cells. However, these CD8⁺ T cells commonly display an exhaustion phenotype with high expression of programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing-3, and/or lymphocyte-activation gene 3, producing low levels of perforin (PRF1) and granzyme B (GZMB), as well as anti-tumor cytokines, such as interferon gamma and tumor necrosis factor alpha. In the referenced study, the authors also showed that deprivation of glutamine decreased the antitumor function of CD8⁺ T cells, as well as the production of PRF1 and GZMB. However, the role of each amino acid in T cell function and exhaustion may depend on tumor type and tumor microenvironment, including the source of other nutrients. Overall, amino acids or other nutrient metabolites in the tumor microenvironment play a pivotal role in both tumor growth and immune response.     

CD4+T细胞在肝细胞癌中的作用

CD4+T细胞为一系列多功能细胞,研究发现肝细胞癌(HCC)中大部分CD4+T细胞亚群可通过活化或抑制机体固有免疫细胞、适应性免疫细胞及非免疫细胞等,参与肿瘤血管生成及浸润、肿瘤细胞凋亡、急性期蛋白及促癌基因的表达,进而发挥肿瘤促进或抑制作用.     

PD-1在肝细胞癌肿瘤浸润淋巴细胞中的表达及与预后的相关性

背景与目的:程序性死亡[蛋白]-1(programmed death-1,PD-1)在调节外周免疫耐受中发挥重要作用,PD-1在肝细胞癌(hepatocellular carcinoma,HCC)肿瘤浸润淋巴细胞中的表达状态与效应细胞CD8+T淋巴细胞的关系尚不清楚,探讨HCC肿瘤浸润淋巴细胞中PD-1的表达及预后意义...     

Clinico-histological and molecular features of hepatocellular carcinoma from nonalcoholic fatty liver disease

Patients with nonalcoholic fatty liver disease (NAFLD) continue to increase with the epidemics of obesity, and NAFLD is estimated to become the most prevalent etiology of hepatocellular carcinoma (HCC). Recently, NAFLD-HCC has been recognized to have clinico-histologically and molecularly distinct features from those from other etiologies, including a lower incidence rate of HCC and less therapeutic efficacy to immune checkpoint inhibitors (ICIs). Consistent with the clinical observations that up to 50% of NAFLD-HCC occurs in the absence of cirrhosis, the imbalance of pro- and antitumorigenic hepatic stellate cells termed as myHSC and cyHSC can contribute to the creation of an HCC-prone hepatic environment, independent of the absolute fibrosis abundance. Immune deregulations by accumulated metabolites in NAFLD-affected livers, such as a fatty-acid-induced loss of cytotoxic CD4 T cells serving for immune surveillance and “auto-aggressive” CXCR6+ CD8 T cells, may promote hepatocarcinogenesis and diminish therapeutic response to ICIs. Steatohepatitic HCC (SH-HCC), characterized by the presence of fat accumulation in tumor cells, ballooned tumor cells, Mallory–Denk body, interstitial fibrosis, and intratumor immune cell infiltration, may represent a metabolic reprogramming for adapting to a lipid-rich tumor microenvironment by downregulating CPT2 and leveraging its intermediates as an “oncometabolite.” Genome-wide analyses suggested that SH-HCC may be more responsive to ICIs given its mutual exclusiveness with β-catenin mutation/activation that promotes immune evasion. Thus, further understanding of NAFLD-specific hepatocarcinogenesis and HCC would enable us to improve the current daily practice and eventually the prognoses of patients with NAFLD.     

中晚期肝癌免疫治疗现状与前景

近年来,随着肿瘤免疫治疗的飞速发展及对肝癌免疫微环境认识的不断深入,以免疫检查点抑制剂为导向的新型系统治疗越来越受到关注。除此之外还有免疫治疗方法如肿瘤疫苗、溶瘤病毒、细胞因子等传统免疫方法也在肿瘤治疗中发挥着一定作用。而基于当前的多学科协作诊疗模式,肝癌的免疫治疗更多强调联合治疗,目前免疫联合治疗的方向主要有:双免疫检查点抑制剂联合、免疫检查点联合放化疗、免疫检查点联合抗血管生成药物等。对于肝癌的免疫治疗呈现了多方案的局面。因此,本文就肝癌免疫治疗的现状与前景进行综述,以期助于临床更好的应用。     

Immunotherapy for nonalcoholic fatty liver disease-related hepatocellular carcinoma: Lights and shadows

About one-fourth of adults globally suffer from nonalcoholic fatty liver disease (NAFLD), which is becoming a leading cause of chronic liver disease worldwide. Its prevalence has rapidly increased in recent years, and is projected to increase even more. NAFLD is a leading cause of hepatocellular carcinoma (HCC), the sixth-most prevalent cancer worldwide and the fourth most common cause of cancer-related death. Although the molecular basis of HCC onset in NAFLD is not completely known, inflammation is a key player. The tumor microenvironment (TME) is heterogeneous in patients with HCC, and is characterized by complex interactions between immune system cells, tumor cells and other stromal and resident liver cells. The etiology of liver disease plays a role in controlling the TME and modulating the immune response. Markers of immune suppression in the TME are associated with a poor prognosis in several solid tumors. Immunotherapy with immune checkpoint inhibitors (ICIs) has become the main option for treating cancers, including HCC. However, meta-analyses have shown that patients with NAFLD-related HCC are less likely to benefit from therapy based on ICIs alone. Conversely, the addition of an angiogenesis inhibitor showed better results regarding the objective response rate and progression-free survival. Adjunctive diagnostic and therapeutic strategies, such as the application of novel biomarkers and the modulation of gut microbiota, should be considered in the future to guide personalized medicine and improve the response to ICIs in patients with NAFLD-related HCC.     

OX40与OX40L在肝细胞肝癌组织中的表达水平及临床意义

目的:探讨OX40(CD134)和OX40L(CD134L)在肝细胞肝癌(hepatocellular carcinoma,HCC)组织中的表达水平及临床意义.方法:收集54例病理明确诊断为HCC患者病理组织,采用免疫组化法检测HCC组织中OX40与OX40L的表达程度,结合临床病理资料分析其在HCC组织中的临床意义及...