CD4^＋T细胞与肿瘤免疫

CD4^＋T细胞不仅辅助激活CD8^＋T细胞,而且对记忆性细胞毒性T淋巴细胞（CTL）应答的产生和维持起重要作用,并具有直接的抗肿瘤功能。另外CD4^＋CD25^＋调节性T细胞（Tregs）具有免疫负调控功能。在肿瘤免疫抑制及免疫逃逸中发挥重要作用,是肿瘤免疫治疗失败的重要原因。近年肿瘤免疫治疗已获得很大进步,相关肿瘤疫苗的研究也备受关注.     

CD4~+T 细胞与肿瘤免疫

CD4~+T细胞不仅辅助激活CD8~+T细胞,而且对记忆性细胞毒性T淋巴细胞(CTL)应答的产生和维持起重要作用,并具有直接的抗肿瘤功能.另外,CD4~+CD25~+ 调节性T细胞(Tregs)具有免疫负调控功能,在肿瘤免疫抑制及免疫逃逸中发挥重要作用,是肿瘤免疫治疗失败的重要原因.近年肿瘤免疫治疗已获得很大进步,相关肿瘤疫苗的研究也备受关注.     

癌相关CD8+记忆T细胞在过继免疫治疗中的应用

针对癌症患者的过继免疫治疗是临床肿瘤治疗研究中的热点话题。癌症患者体内天然存在着能够对恶性肿瘤细胞进行识别、攻击和杀伤的癌相关CD8+记忆T细胞,它们具有对少量肿瘤细胞产生快速免疫应答和持续长期发挥抗癌作用的优点。癌相关CD8+记忆T细胞主要存在于骨髓中,如将骨髓中的这部分T细胞分离出来,并以特定手段激活并回输体内,将可发挥强大的免疫治疗作用。为了帮助临床癌症治疗研究者们更加清晰地认识癌相关CD8+记忆T细胞的生物学特性、肿瘤杀伤能力和临床治疗效果,并妥善处理实际应用过程中遇到的各种问题,本文对近年有关癌相关CD8+记忆T细胞在肿瘤免疫治疗中应用的研究进展加以介绍。     

CD200在恶性肿瘤作用中的研究进展

肿瘤免疫治疗是肿瘤治疗中一种非常有前景的治疗手段，包括主动免疫治疗、过继细胞转移治疗和免疫检查点阻断治疗。CD200作为一种免疫耐受信号分子，在维持机体自身免疫耐受中发挥重要作用。近年来，研究显示免疫检查点CD200及其受体CD200R在多种肿瘤中异常表达，且与肿瘤的侵袭、转移及患者预后不良相关，此外CD200/CD200R过度激活在抑制抗肿瘤免疫应答中发挥重要作用，这展现了其在肿瘤免疫治疗中的潜力。本文就CD200的结构、生物学功能及其在肿瘤免疫治疗前景的研究进展进行综述。     

干细胞样CD8+ T细胞：肿瘤免疫疗法的新生力量

CD8+ T 细胞是抗肿瘤免疫应答的主要执行者。通过重塑CD8+ T 细胞杀伤肿瘤细胞的能力，免疫疗法已在抗肿瘤领域取得重大突破，但临床获益仅局限于部分患者和癌症类型。如何克服CD8+ T细胞功能障碍是肿瘤免疫疗法亟待解决的关键问题。近年来，多项研究揭示了CD8+ T细胞的干性调控机制，发现了干细胞样CD8+ T细胞具有自我更新和增殖能力，阐明了该细胞亚群在维持持续性肿瘤免疫治疗应答中的重要性。本文论述了干细胞样CD8+ T 细胞的分子与功能特征、CD8+ T 细胞干性的细胞内外影响因素，归纳总结了目前靶向CD8+ T细胞的干性重编程策略，进一步展望了靶向CD8+ T细胞干性程序来提高肿瘤免疫疗法疗效的思路和方法。     

鼻咽癌患者放疗前后外周血EBV-DNA和细胞免疫水平的研究

摘要：目的比较鼻咽癌（NPC）患者放疗前后抗EBV特异性CTL细胞免疫功能、EBV-DNA、T细胞亚群及CD4+CD25+Tr淋巴细胞水平,为临床选择免疫治疗方案及预测预后提供理论依据及客观指标。方法收集标本105份（NPC患者放疗前35份、NPC患者放疗6月后40份和健康人30份）,ELISPOT检测外周血LMP2特异性CTL;荧光定量PCR检测EBV-DNA;流式细胞术检测T细胞亚群及CD4+CD25+Tr淋巴细胞,统计分析各指标变化的特点及相互关系。结果抗EBV-LMP2特异性细胞免疫反应最大频率见于健康对照组,NPC放疗前患者中则仅少数呈阳性反应,NPC放疗后组反应率介于NPC放疗前组和健康对照组之间;NPC放疗前组血清EBV-DNA的阳性率均高于其他两组,对EBV-LMP2特异性细胞免疫反应的阳性率与血清中EBV-DNA病毒载量的阳性率呈负相关;放疗前NPC患者外周血CD3+、CD4+T细胞百分率及CD4+/CD8+比值降低, CD8+T细胞百分率升高,CD4+CD25+Tr细胞水平升高,放疗后情况有所缓解。结论EBV-LMP2特异性CTL反应在NPC放疗前患者最低,EBV-LMP2特异性CTL反应阳性率与血清中EBV-DNA载量相关,增强CTL应答可改善EBV相关肿瘤的治疗效果,EBV-DNA载量水平一定程度上可反映NPC患者的肿瘤负荷。NPC患者外周血CD3+、CD4+T细胞降低,而CD8+T细胞升高,CD4+CD25+Tr细胞比例升高,监测患者T细胞亚群有助于对NPC患者的治疗及预后的判断。     

中央记忆型T细胞与肿瘤免疫治疗的相关性研究进展

记忆T细胞（memory T cell,Tm）作为人体免疫系统中的一个组成部分，在免疫应答中发挥着至关重要的作用。中央记忆型T细胞（central memory T cell,Tcm）是幼稚T细胞经过抗原激活后，产生的具有长期记忆性的、并能够归巢到淋巴结接受抗原再刺激的T细胞。肿瘤免疫治疗的抗肿瘤作用及不良反应的发生与T细胞功能密切相关，Tcm不仅是介导免疫应答的防线，其作为疗效预测生物标记物的研究也取得了相当大的进展。目前肠道菌群对肿瘤免疫治疗的影响备受关注，肠道菌群及其代谢产物通过影响肿瘤微环境调控疗效，其在免疫细胞层面的机制值得探究。本文对Tcm在组织中的分化、表面标记，在肿瘤免疫治疗中的作用及其与肠道菌群的联系等方面的研究进展进行综述。     

组织驻留CD8+T细胞在肿瘤中的研究进展

组织驻留记忆 T 细胞（ tissue-resident memory T cells，TRMs）作为一种特殊的记忆T细胞，在免疫应答中发挥着极其重要的作用。其特征是可表达归巢受体，从而具备驻留特性，因此能够驻留在外周组织器官中，当病原体侵袭时可以迅速反应。目前，TRMs（尤其是CD8+TRMs）与肿瘤的关系及其在抗肿瘤中的应用被愈加重视，一方面是CD8+TRMs可以通过分泌颗粒酶B、穿孔素和INF-γ等因子直接杀伤肿瘤细胞，另一方面一些抗肿瘤措施（如放化疗、免疫治疗等）可以使CD8+TRMs在肿瘤组织中富集，从而进一步提高治疗的效果。本文就CD8+TRMs的亚群分类、在肿瘤中如何调控形成以及其在肿瘤治疗中的作用等方面的研究进展进行综述。      

Th17细胞及其在肿瘤免疫中作用的最新进展

人体免疫系统是由固有免疫和适应性免疫应答组成。适应性免疫应答在抗原入侵时扮演着至关重要的角色,而CD4 + 辅助性T（CD4 + T helper, CD4 + Th）细胞是适应性免疫应答的主要组成部分。最近新发现的一类不同于Th1和Th2细胞亚群且能 特征性分泌白细胞介素17 (interleukin-17, IL-17)的辅助性T细胞亚群,被命名为Th17细胞。Th17 细胞参与很多炎症性疾病、自 身免疫性疾病和肿瘤等的发展过程,可通过分泌IL-17A、IL-17F、IL-21、IL-22、IL-23、粒细胞-巨噬细胞克隆刺激因子(granulocyte- macrophage colony stimulating factor,GM-CSF)和干扰素γ （interferon-gamma,IFN-γ）等炎症细胞因子来发挥免疫效应和炎症效 应。但是Th17细胞是否参与肿瘤的发生发展、具体作用机制以及发挥促肿瘤还是抑肿瘤效应等问题存在很多争议。本文综述 了近年来Th17细胞分化调节过程的相关机制,以及其在肿瘤发生发展的作用,旨在为肿瘤的诊断和治疗提供新的思路。     

调节性T细胞与肿瘤免疫

调节性T细胞( Treg)是一类有负调节作用的T细胞亚群,包括CD4+ Treg、CD8+ Treg、NKT Treg和DN Treg细胞等4大类,主要发挥抑制性免疫调节功能,是肿瘤免疫逃逸的重要因素.这些机制包括分泌多种免疫抑制性细胞因子、分泌颗粒酶和穿孔素杀伤效应细胞、竞争和抑制IL-2、通过T淋巴细胞毒性相关抗原(CTLA)-4影响Treg的分化和增殖等.以Treg及免疫抑制性分子作为靶点,清除Treg,控制Treg的数量和功能,增强机体对肿瘤的免疫应答,为肿瘤免疫治疗提供了新思路.     

ILC2s在肿瘤免疫调控中的研究进展

Ⅱ型固有淋巴细胞(Type 2 innate lymphoid cells, ILC2s)是一类独特的免疫效应细胞,在抗感染、调控炎症和维持免疫稳态中起着重要作用。近期研究表明ILC2s也参与调节肿瘤免疫,在肿瘤微环境中发现了ILC2s,但是目前ILC2s在肿瘤免疫反应和免疫治疗中的作用尚未阐明。有研究表明白细胞介素33(IL-33)可以激活肿瘤微环境中的ILC2s, ILC2s表达抑制性检查点受体PD-1,PD-1阻断剂直接作用于ILC2s,减轻ILC2s细胞固有的PD-1抑制,最终增加了肿瘤组织CD8⁺细胞毒性T淋巴细胞(Cytotoxic T lymphocyte, CTL)浸润,增强了肿瘤免疫反应,活化的肿瘤ILC2s可以作为抗PD-1免疫疗法的靶标。本文就目前ILC2s参与调控肿瘤免疫可能的机制,探讨新的肿瘤免疫检查点抑制剂靶点进行综述。     

DC—CIK细胞免疫治疗骨肉瘤的研究进展

骨肉瘤是由肿瘤细胞直接形成骨或骨样组织为特征的骨骼原发恶性肿瘤,其较长见于儿童和青少年,好发于长骨的干骺端,其中股骨远端或胫骨近端多见,其次为肱骨近端,随着血液运行转移率高且早,发展迅速。以往骨肉瘤患者的临床预后差,即使选择截肢手术治疗,5年内生存率也仅为20％左右。近年来,由于多种化疗药物的发现,患者生存率得到明显提高,同时使得骨肉瘤患者的保肢治疗已成为主要趋势,对于原发无转移的患者,约70％患者可以获得长期生存。     

PD1-TCF1+CD8+干细胞样记忆T细胞对肿瘤患者免疫预后及三级淋巴结构的影响

Objective To investigate the impact of PD1-TCF1+CD8+ stem-like memory T cells on immunotherapy prognosis and tertiary lymphoid structure in tumors. Methods Pathological tissue sections were collected from 33 patients treated with immunotherapy, 18 cases of NSCLC and 15 cases of ESCC. The expression of PD1-TCF1+CD8+T cells was detected through quantitative analysis by multiplex immunofluorescence. Survival curves were described by the Kaplan-Meier method. Pearson’s correlation test was used for correlation analysis. Results The high levels of PD1-TCF1+CD8+T cells had a better PFS in NSCLC and ESCC cohorts. In the NSCLC cohort, high levels of PD1-TCF1+CD8+ T cells were significantly and positively correlated with the number (P=0.0151) and size (P=0.0007) of TLSs. Conclusion In patients with NSCLC and ESCCs, high PD1-TCF1+CD8+ stem-like memory T cell expression indicates improved prognosis and immune response and is associated with the formation of TLSs in the tumor microenvironment of NSCLC. © 2023, CHINA RESEARCH ON PREVENTION AND TREATMENT. All rights reserved.     

Glucocorticoid-induced tumor necrosis factor receptor stimulation enhances the multifunctionality of adoptively transferred tumor antigen-specific CD8+ T cells with tumor regression

We have reported for the first time the significance of effector T-cell multifunctionality in antitumor immunity, suggesting that the appearance of multifunctional/polyfunctional tumor-specific CD8⁺ T cells in vivo is a critical determinant of the success of antitumor immunotherapy, and a strategy to induce multifunctionality in effector cells is required for the successful immunotherapy of hosts with progressing tumor. Glucocorticoid-induced tumor necrosis factor receptor (GITR) stimulation has been shown to enhance antitumor immune response. However, its functional impact on adoptively transferred T cells remains unclear. Here, we analyzed the impact of GITR stimulation in vivo on the functional profiles of adoptively transferred CD8⁺ T cells specific for murine fibrosarcoma CMS5. GITR stimulation was found to enhance multifunctionality (interferon (IFN)-γ and tumor necrosis factor (TNF)-α production and CD107a mobilization as a degranulation marker) in transferred cells at the single-cell level. These cells exhibited upregulated expression of CD25 in draining lymph nodes and increased infiltration in tumor. Mice that received T-cell therapy with GITR stimulation showed reduced Foxp3⁺CD4⁺ T cells among tumor infiltrating lymphocytes and increased in vivo cytotoxic T lymphocytes (CTL) activity even with progressing tumor, resulting in enhanced tumor regression. These data strengthen the idea that effector T-cell multifunctionality is a sensitive immune correlate for successful immunotherapy against malignancy and provide an immunological rationale for effective T-cell therapy combined with GITR stimulation. ( Cancer Sci 2009; 100: 1317–1325)     

High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer

In a prospective study, we have examined the tumor-specific immune response in a group of 59 patients with human papillomavirus (HPV) 16-positive (HPV16(+))-induced or HPV18(+)-induced cervical cancer. Local antitumor immunity was analyzed by the enumeration of tumor-infiltrating dendritic cells and CD4+, CD8+, and regulatory T cells as well as by calculation of the ratio of CD8+/CD4+ T cells and CD8+/regulatory T cells. Systemic tumor-specific immunity was assessed by determination of the HPV E6- and/or E7-specific T-cell response in the blood of these patients. Finally, these variables were evaluated with respect to known histopathologic prognostic variables, including the absence (LN-) or presence (LN+) of lymph node metastases. Stratification according to the lymph node status of patients revealed a significantly stronger CD8+ T-cell tumor infiltration, a higher CD8+/CD4+ T-cell ratio, and higher CD8+/regulatory T-cell ratio in the group of patients in which the tumor failed to metastasize to the tumor-draining lymph node. Subdivision according to the presence (IR+) or absence (IR-) of circulating HPV-specific T cells disclosed that the highest number of tumor-infiltrating CD8+ T cells was found in the group of LN- patients displaying a concomitant systemic tumor-specific immune response (LN-IR+). CD8+ T-cell infiltration in LN-IR- patients was comparable with that of LN+ patients. In cervical cancer, the absence of lymph node metastases is strongly associated with a better prognosis. Our data indicate that, especially in a subgroup of LN- patients, a strong and effective interaction between immune system and tumor exists. This subgroup of cervical cancer patients may have the best prognosis.     

Hyperthermia improves cellular immune response to human hepatocellular carcinoma subsequent to co-culture with tumor lysate pulsed dendritic cells

Dendritic cells play a major role in cellular immunity. The crucial steps of antigen presentation and processing by DCs may be limiting factors for adoptive cellular immunotherapy. Here, we investigated whether hyperthermia of human hepatocellular carcinoma (HCC) cells induces enhanced cytotoxic cellular immune response. Peripheral blood mononuclear cell (PBMC)-derived DCs were pulsed with tumor cell lysate of the human HCC cell line HepG2, which had been heat shocked prior to incubation for 5 h. Subsequent to TNFalpha-induced maturation DCs were co-cultured with autologous CD4+ and/or CD8+ cells, and T cell mediated cytolysis of HepG2 cells was assessed. We observed enhanced CD4+/8+ cellular cytotoxicity against HepG2 cells subsequent to co-culture with the heat shocked tumor lysate pulsed DCs as compared to pulsing DCs with lysate of non-heat shocked tumor cells. The improved cellular immune response can be related to enhanced expression of HSP 70 and 90 in HepG2 cells upon hyperthermia.     

Development of Vaccine Strategies for the Treatment of B-Cell Malignancies

INTRODUCTION Early observations suggesting some cancer patients can mount a therapeutic immune response to their own tumors (reviewed in Ref. 1) have supported long-standing efforts to develop immunotherapy regimens for the adjunct treatment of human neoplastic disease. Immunotherapy protocols are classified as either passive or active specific, depending on how they are designed to deliver the desired immunity to the patient. Passive immunotherapy regimens are characterized by the passive administration of immune effector components such as lymphokines, antibodies, cytotoxic T cells, or lymphocyte-activated-killer (LAK) cells. By contrast, active specific immunotherapy (ASI) regimens actively induce effector mechanisms and tumor immunity in the patient by deliberate vaccination with a tumor cell or its antigenic components. The ASI approach is preferred because the resulting immunity is longer lasting, and a potential memory response may provide beneficial immune surveillance in the host against further outgrowth of the tumor.     

CD4+ T lymphocytes play a critical role in antibody production and tumor immunity against simian virus 40 large tumor antigen

The role of CD4+ T lymphocytes in antitumor immunity has been largely attributed to providing signals required for the priming of MHC class I-restricted CD8+ cytotoxic T lymphocytes, and CD8+ cytotoxic T lymphocytes are thought to serve as the predominant mediators of tumor killing in vivo. We decided to evaluate the role of T lymphocyte subsets in tumor immunity induced by recombinant SV40 large tumor antigen (Tag) within an experimental murine pulmonary metastasis model of SV40 Tag-expressing tumors. Studies in BALB/c mice used in vivo depletion of either CD4+ or CD8+ T cells in the induction phase of the immune response to SV40 Tag. These studies indicate that CD4+ T cells but not CD8+ T cells were critical in the production of antibodies to SV40 Tag and in tumor immunity as the result of recombinant SV40 Tag immunization. On the basis of the predominance of the IgG1 isotype in the antibody response to SV40 Tag immunization, Th2 type CD4+ T cells appeared to be involved. SV40 Tag immunization was not as effective in the induction of tumor immunity in therapeutic modalities when compared with the prophylactic setting. Our results suggest that CD4+ T cells, along with antibody responses, play a role in the induction of tumor immunity to a viral-encoded tumor antigen.