放疗与免疫治疗联合应用的相关机制及研究进展

放疗主要通过对放射野内肿瘤细胞的杀伤来提高肿瘤的局部控制、降低远处播散并能够激活机体抗肿瘤免疫应答,在免疫治疗的辅助下发挥全身抗肿瘤的作用。放疗联合免疫治疗作为一种新的治疗方式在部分转移性癌症患者中取得了显著疗效。在放射线杀伤局部肿瘤细胞的过程中,肿瘤相关抗原释放表达增加、肿瘤免疫抑制微环境得到改善、激活特异性T细胞免疫应答促使肿瘤细胞形成原位疫苗,合适的放疗剂量与分割模式在最佳时机联合相应的免疫治疗可杀伤放疗野外的远处转移病灶。本文对放疗促进抗肿瘤免疫反应的具体机制以及两者联合应用的广阔前景和面临的挑战进行综述。      

放疗协同免疫检查点阻滞剂治疗肿瘤的机制

随着对肿瘤免疫机制的深入研究,学者们注意到了放疗激活机体产生全身免疫效应的现象,改变了放疗是“免疫抑制性”的片面认识.然而,放疗虽能增强机体的抗肿瘤免疫,在临床上,接受放疗的患者仍避免不了复发、转移.研究表明,这与肿瘤微环境诱导的免疫检查点通路异常激活密切相关.因此,将放疗与免疫检查点阻滞剂联合应用,改善肿瘤微环境,能提高肿瘤治疗效果.     

肿瘤放疗对免疫功能的影响

肿瘤放疗能够影响机体免疫,最新研究显示适当的放疗方式能够通过调节肿瘤微环境、激活免疫细胞、释放死亡危险信号而激活免疫,产生旁观者或远位效应。随着放疗与免疫联合治疗临床评价指标研究及临床试验的开展,将有望改变传统的肿瘤治疗模式。     

放疗免疫调节效应研究的进展——从基础到临床

既往观点认为，放射治疗主要通过破坏肿瘤细胞脱氧核糖核酸双链直接发挥杀伤肿瘤细胞的作用，近年来研究发现，放疗也可通过上调局部与全身免疫反应，间接产生积极有效的抗肿瘤免疫应答。然而，放疗的免疫调节效应具有双面性，一方面可激活并产生抗肿瘤免疫促进效应，另一方面也可能产生免疫抑制作用。其中，放疗正向调节适应性与固有性抗肿瘤免疫反应的关键分子机制主要包括：诱导免疫原性细胞凋亡从而促进T淋巴细胞的增殖与活化；激活环磷酸鸟苷-腺苷合成酶-干扰素基因刺激蛋白通路引发Ⅰ型干扰素反应；改变肿瘤细胞表型，加强其免疫原性与抗原可视度；刺激肿瘤细胞与基质细胞释放多种炎症因子，重塑肿瘤免疫微环境；上调肿瘤细胞表面免疫检查点以及死亡受体等的表达，促进免疫识别与抗肿瘤免疫应答。而放疗负向抑制免疫反应的主要机制包括：诱导肿瘤细胞上调多种免疫抑制因子的基因表达；增强包括调节性T细胞、髓系来源抑制性细胞在内的多种免疫抑制细胞的功能与作用；导致淋巴细胞的数量减少以及免疫效应细胞的耗竭等。基于以上关于放疗免疫调节效应的机制原理探索，目前在放疗联合免疫治疗的临床实践中也显示出重大的研究进展，包括免疫治疗时代背景下的放疗远隔效应，...     

肿瘤排斥抗原肽的研究进展

肿瘤来源于自身组织 ,但大量的免疫学研究表明机体确实存在着特异性的肿瘤抗原 ,激活机体抗肿瘤免疫应答 ,其中主要是Ｔ淋巴细胞介导的特异应答。肿瘤排斥抗原肽 (ｔｕｍｏｒｒｅｊｅｃｔｉｏｎａｎｔｉｇｅｎｐｅｐ ｔｉｄｅ ,ＴＲＡＰ)是指在这一免疫应答过程中由ＭＨＣ分子递呈多肽片段 ,可特异性激活Ｔ淋巴细胞 ,从而参与机体特异性的抗肿瘤免疫反应。免疫学研究表明 ,这些与Ｔ淋巴细胞特异结合的肽片段是在免疫过程中真正起激活作用的物质。可以看出 ,ＴＲＡＰ在肿瘤的免疫治疗方面有着广阔的应用前景。近几年 ,在肿瘤排斥抗原肽的获取…     

晚期非小细胞肺癌免疫检查点抑制剂联合立体定向放疗研究进展

放疗对机体抗肿瘤免疫效应的影响具有双向性,免疫治疗尤其是免疫检查点抑制剂(ICIs)与放疗联合可产生抗肿瘤免疫的协同作用。与常规放疗相比,体部立体定向消融放疗(SABR)可对靶病灶实现高精度和高剂量照射,具有更强的抗肿瘤免疫激活效应,同时因剂量梯度陡峭,可较好的保护周围正常组织,是晚期非小细胞肺癌(NSCLC)迅速控制...     

代谢重编程介导肿瘤微环境免疫抑制的研究评述

近十年免疫疗法在肿瘤的治疗中取得了突破性进展,导致肿瘤治疗的范式转变。然而大多数患者并不能从中获益,如何提高患者免疫治疗的应答率是亟待解决的热点问题。免疫疗法的成功有赖于机体免疫效应细胞的活化及杀伤效应。然而,在肿瘤微环境严苛的代谢和营养应激下,免疫细胞的功能常处于紊乱状态,导致抗肿瘤免疫应答受损。因此,通过靶向肿瘤代谢重塑免疫微环境,恢复抗肿瘤免疫应答,有望在与免疫疗法的联合应用中取得协同效应。本文着重探讨代谢重编程及其代谢产物如何调节抗肿瘤免疫应答,旨在为肿瘤免疫治疗提供新的思路和方法。     

代谢重编程介导肿瘤微环境免疫抑制的研究评述

近十年免疫疗法在肿瘤的治疗中取得了突破性进展,导致肿瘤治疗的范式转变。然而大多数患者并不能从中获益,如何提高患者免疫治疗的应答率是亟待解决的热点问题。免疫疗法的成功有赖于机体免疫效应细胞的活化及杀伤效应。然而,在肿瘤微环境严苛的代谢和营养应激下,免疫细胞的功能常处于紊乱状态,导致抗肿瘤免疫应答受损。因此,通过靶向肿瘤代谢重塑免疫微环境,恢复抗肿瘤免疫应答,有望在与免疫疗法的联合应用中取得协同效应。本文着重探讨代谢重编程及其代谢产物如何调节抗肿瘤免疫应答,旨在为肿瘤免疫治疗提供新的思路和方法。     

刺激疗法的免疫学基础

Ehrlich早在本世纪初就发现免疫系统具有抗肿瘤的作用,Thomas在五十年代中期论证了这一观点,Burnet于七十年代初正式提出免疫监视概念,认为机体免疫系统能够识别并通过细胞免疫机制破坏肿瘤细胞.肿瘤免疫治疗即是采用主动或被动免疫手段,干预宿主免疫应答,增强机体抗肿瘤能力.自Luckey(1980年)和Olivieri(1984年)提出低剂量辐射可诱导生物体的兴奋效应和适应性反应以来,国内外学者广泛开展了低剂量辐射与免疫的研究,并于1987年在德国法兰克福召开了“低剂量辐射与免疫系统专题讨论会”.鉴于低剂量辐射诱发的适应性可提高治疗比,其刺激增强的免疫功能对肿瘤的杀灭效应又是有益的补充,为此笔者曾根据资料提出刺激疗法这一新概念,并论证了其临床应用的可行性.本文旨在探讨其增强放疗治癌效果的免疫学基础.多年来,人们通过总结大宗的临床病例,对放疗的治癌作用已深信不疑,目前,肿瘤患者的治疗70%以上需行放疗.然而,放疗对肿瘤病人免疫功能的抑制却一直困扰着人们,文献报道:肿瘤病人放疗后,由于免疫细胞对射线敏感     

放射治疗联合免疫疗法治疗恶性肿瘤的相关机制与研究进展

放射治疗能通过诱导 DNA 损伤杀伤照射野内的肿瘤细胞,也能激活机体免疫系统。放疗可促进肿瘤相关抗原释放、激活树突状细胞并促进肿瘤相关抗原的呈递、增加肿瘤浸润淋巴细胞,刺激免疫系统阻止肿瘤的复发和（或）转移。一些研究已证实放疗与免疫治疗联合可发挥协同抗肿瘤效应。本文就放疗与免疫治疗联合应用抗肿瘤的相关机制及最新研究进展做一综述。     

Culture of TCGF-dependent immunosuppressor T cells in gastric cancer patients and phenotypic characterization of the cell surface, using monoclonal antibodies and a fluorescence-activated cell sorter (FACS)

We cultured immunosuppressor T cells from gastric cancer patients using T-cell growth factor (TCGF) prepared from human tonsil or spleen. Peripheral blood lymphocytes cultured for 3-4 weeks with TCGF strongly inhibited the lymphocyte-proliferative response to alloantigen or PHA. Quantitative fluorescence measurement for immunological analysis of phenotypic characterization of the cells was made on a FACS-IV, using monoclonal antibodies (anti Leu-I, anti Leu-2a, anti Leu-3a, anti Leu-4, anti Leu-5, anti Leu-7, anti HLA-DR) and goat anti-human immunoglobulin. Immunosuppressor T cells grown in the presence of TCGF showed phenotype Leu-1+, 2a+, 3a-, 4+, 5+, 7-, HLA-DR+, human Ig-. Culture of immunosuppressor T cells activated by tumor cell antigen in vitro was successful only when the cells derived from patients with disseminated, nonresectable type of gastric carcinoma. Our findings suggest that TCGF-dependent immunosuppressor T cells are the result of a large tumor burden; this may explain the depression of in vitro or in vivo cell-mediated immune responses frequently found in such cancer patients.     

Treg 细胞与乳腺癌的研究进展

CD4＋CD25＋调节性T细胞是一类具有特殊免疫调节功能的T细胞亚群,在机体免疫稳态维持、肿瘤免疫以及移植耐受等方面发挥着重要的作用。最近,大量的研究发现CD4＋CD25＋调节性T细胞在乳腺癌患者外周血和组织中表达增加,与肿瘤的发生、发展密切相关。本文就CIM＋CD25＋调节性T细胞与乳腺癌的关系作一简要综述。     

人参皂苷抗结直肠癌作用机制的研究进展

人参皂苷作为人参的主要活性成分,具有诱导肿瘤细胞调亡、抑制肿瘤细胞增殖、诱导细胞周期停滞、抑制肿瘤血管生成、免疫调节、化疗增效、抗炎以及调节肠道菌群等作用。现如今,人参皂苷对结直肠癌的作用已成为研究的热点。文章就人参皂苷抗结直肠癌的作用机制进行综述。     

A novel RNA‐based adjuvant combines strong immunostimulatory capacities with a favorable safety profile

Protein‐ and peptide‐based tumor vaccines depend on strong adjuvants to induce potent immune responses. Here, we demonstrated that a recently developed novel adjuvant based on a non‐coding, long‐chain RNA molecule, termed RNAdjuvant^®, profoundly increased immunogenicity of both antigen formats. RNAdjuvant^® induced balanced, long‐lasting immune responses that resulted in a strong anti‐tumor activity. A direct comparison to Poly(I:C) showed superior efficacy of our adjuvant to enhance antigen‐specific multifunctional CD8⁺ T‐cell responses and mediate anti‐tumor responses induced by peptide derived from HPV‐16 E7 protein in the syngeneic TC‐1 tumor, a murine model of human HPV‐induced cervical cancer. Moreover, the adjuvant was able to induce functional memory responses that mediated complete tumor remission. Despite its remarkable immunostimulatory activity, our RNA‐based adjuvant exhibited an excellent pre‐clinical safety profile. It acted only locally at the injection site where it elicited a transient but strong up‐regulation of pro‐inflammatory and anti‐viral cytokines as well as cytoplasmic RNA sensors without systemic cytokine release. This was followed by the activation of immune cells in the draining lymph nodes. Our data indicate that our RNA‐based adjuvant is a safe and potent immunostimulator that may profoundly improve the efficacy of a variety of cancer vaccines.     

Targeting myeloid-derived suppressor cells for cancer therapy

The emergence and clinical application of immunotherapy is considered a promising breakthrough in cancer treatment. According to the literature, immune checkpoint blockade (ICB) has achieved positive clinical responses in different cancer types, although its clinical efficacy remains limited in some patients. The main obstacle to inducing effective antitumor immune responses with ICB is the development of an immunosuppressive tumor microenvironment. Myeloid-derived suppressor cells (MDSCs), as major immune cells that mediate tumor immunosuppression, are intimately involved in regulating the resistance of cancer patients to ICB therapy and to clinical cancer staging and prognosis. Therefore, a combined treatment strategy using MDSC inhibitors and ICB has been proposed and continually improved. This article discusses the immunosuppressive mechanism, clinical significance, and visualization methods of MDSCs. More importantly, it describes current research progress on compounds targeting MDSCs to enhance the antitumor efficacy of ICB.     

脐带血树突状细胞对小鼠S-180移植瘤的作用研究

目的 :观察脐带血树突状细胞对小鼠S - 180细胞株移植瘤的作用。方法 :采用脐带血来源的单核细胞制备树突状细胞 ,体外经S - 180细胞肿瘤相关抗原 (TAA)致敏后免疫小鼠 ,一周后接种S - 180细胞株。或先制备荷瘤小鼠模型 ,一周后再接种致敏树突状细胞。结果 :脐带血来源的树突状细胞经胃癌细胞系S - 180的TAA致敏后既能明显保护小鼠该移植瘤的发生 ,又能抑制已发生移植瘤的生长。同对照组相比 ,预防组和治疗组的瘤体积明显缩小 ,细胞免疫功能趋于正常 ,生存期延长 (P <0 0 5 )。结论 :脐带血树突状细胞对小鼠S - 180移植瘤的发生有预防作用 ,对荷瘤小鼠移植瘤的生长有抑制作用 ,为树突状细胞的临床应用提供了进一步的依据     

Circulating human papillomavirus type 16 specific T-cells are associated with HLA Class I expression on tumor cells, but not related to the amount of viral oncogene transcripts

Human papillomavirus (HPV) is a necessary factor in the pathogenesis of cervical cancer. Circulating HPV-specific T-cells responding to the E6 and E7 HPV proteins can be detected only in half of cervical cancer patients. Potential explanations for the absence of this response are lack of sufficient amounts of antigen to activate the immune response or local immune escape mechanisms. We studied the relationship between HPV 16 E6/E7 oncogene mRNA expression, human leukocyte antigen (HLA) expression on tumor cells and the presence of circulating E6- and E7-specific T-cell responses in cervical cancer patients. The amount of antigen was assessed by HPV E6/E7 mRNA expression levels measured by quantitative polymerase chain reaction. HLA Class I and Class II expression on tumor cells was analyzed by immunohistochemistry. A proliferative HPV-specific T-cell response was detected in 15/29 patients. The amount of HPV E6/E7 mRNA was not related to the presence of immune response. HLA Class I expression was downregulated in 19 patients and completely lost in 7 patients. HLA Class II expression was upregulated in 18 patients. HLA Class I expression on tumor cells showed a strong correlation with immunity (p = 0.001). Explicitly, all patients with complete HLA loss lacked HPV specific T-cell responses. The presence of circulating HPV-specific T-cells might reflect ongoing antitumor response that is sustained by CD8+ T-cells killing HLA Class I positive cancer cells. We hypothesize that HLA Class I expression status on tumor cells might as well influence the response to HPV E6/E7 directed immunotherapy.     

树突状细胞体外诱导抗肿瘤免疫通过诱导肿瘤细胞凋亡抑制裸鼠移植瘤生长

研究树突状细胞（ＤＣ）体外诱导的细胞免疫抑制裸鼠移植瘤生长作用及其机理。方法：联合应用粒／巨噬细胞集落刺激因子ＫＭ－ＣＳＦ）及白介素－４（ＩＬ－４）直接从肝癌患者外周血中培养出ＤＣ,以人肝癌细胞系ＨｅｐＧ２肿瘤细胞的肿瘤抗原粗提物刺激ＤＣ,ＤＣ激活同源的Ｔ淋巴细胞,建立裸鼠人肝癌细胞系ＨｅｐＧ２移植瘤模型,以被激活的Ｔ淋巴细胞治疗裸鼠ＨｅｐＧ２移植瘤并观察治疗效果,检测移植瘤标本肿瘤细胞凋亡情况。结果：ＤＣ诱导的Ｔ细胞免疫能够诱导裸鼠人肝癌细胞系ＨｅｐＧ２移植瘤肿瘤细胞大量凋亡从而抑制裸鼠ＨｅｐＧ２移植瘤生长。结论：经肿瘤抗原激活的ＤＣ作为一新概念上的抗肿瘤疫苗有可能在肿瘤的治疗中发挥重要作用。     

The impact of CD4+CD25+ Treg on tumor specific CD8+ T cell cytotoxicity and cancer

There is sufficient evidence to suggest that tumor growth elicits specific immune responses, including CD8(+) and CD4(+) T cell responses that may delay tumor growth and could potentially be harnessed to eradicate cancer. Nevertheless the frequent outcome of cancer is lethality associated with uncontrolled growth and dissemination of tumor cells. The failure of the immune response may be naturally programmed and related to a specific subpopulation of CD4(+)CD25(+) regulatory T cells, whose function is to protect us against autoimmunity. Recent investigations have shed light on the in vivo behavior and functions of these cells. It is becoming evident that a major impact of these cells is on the cytolytic action of specific CD8(+) T cells that target the tumor. Inhibition of cytotoxicity is dependent on TGF-beta signaling by the effector cells. Thus, targeting immune regulation may provide a promising approach to the immune therapy of cancer. This approach however could also have unexpected deleterious consequences, as surprising new observations indicate that regulatory T cells can also delay tumor growth by independent mechanisms that relate to their cross talk with the innate immune response to cancer.     

CpG ODN诱导树突状细胞抗肿瘤作用的研究进展

 CpG ODN是含有CpG基序的脱氧寡核苷酸,它具有强大的免疫调节作用,能够激活自然杀伤（NK）细胞、单核／巨噬细胞、树突状细胞（DC）、B细胞和T细胞等多种免疫细胞,诱导并增强非特异性及特异性免疫应答;同时还可以诱导产生Th1型免疫反应,下调Th2型反应,调控免疫应答类型。DC是目前发现的功能最强的专职抗原提呈细胞,在抗原加工提呈、抗原识别及T细胞激活中发挥重要作用,对多种肿瘤细胞具有杀伤作用。近年来,以DC为基础的肿瘤免疫治疗日益受到人们的重视。现就近年CpG ODN与DC免疫治疗肿瘤的研究进展作一综述。