CD244免疫调节作用及其机制的研究进展

免疫受体CD244是信号淋巴细胞活化分子家族成员,在NK细胞、T细胞、嗜酸性粒细胞的活性调节中具有重要的作用,在感染免疫、炎症发生和肿瘤免疫中也发挥重要的调节作用,因而研究CD244的分子结构、免疫调节作用及其机制对感染和肿瘤的免疫治疗具有重要的意义.     

基于打破树突状细胞耐受的抗肿瘤免疫治疗

树突状细胞(DC)是专职抗原呈递细胞,具有强大的免疫监视功能.由于在诱导免疫反应中的重要作用,DC已被广泛地应用于抗肿瘤免疫治疗.但是由于肿瘤细胞对荷瘤宿主免疫系统,尤其是对DC功能的抑制,使以DC为基础的抗肿瘤免疫治疗疗效受到了很大的限制.所以,通过调节DC功能,可打破肿瘤对DC的免疫抑制,引导有效的抗肿瘤反应,提高以DC为基础的抗肿瘤免疫效果,这在抗肿瘤免疫治疗中具有重要意义.     

肿瘤免疫逃逸和免疫抑制的机制和免疫治疗策略的研究进展

免疫治疗是抗肿瘤治疗的一项重要的辅助治疗手段.有效的激活自身抗肿瘤免疫系统对早期肿瘤的治疗有重要意义.与传统的应用靶点特异性抗体不同,研究者更倾向于对肿瘤组织内部的免疫应答过程进行深入研究,从而期望制定出更有效的肿瘤免疫治疗方案.肿瘤细胞处于不利于诱导抗肿瘤免疫应答的微环境中是肿瘤免疫治疗面临的主要困难之一.     

IL-35及其诱导产生的新型调节性T细胞——iTR35细胞

调节性T细胞(Treg)诱导的免疫逃逸机制是肿瘤发生的关键因素之一.IL-35是一种新发现的主要来源于Treg的抑制性细胞因子,其不仅可以作为Treg的重要效应分子直接参与免疫调节,还可以诱导产生一种新型Foxp3Treg——iTR35细胞,从而在肿瘤免疫逃逸过程中级联放大Treg的免疫调节作用,成为进一步促进肿瘤发展和影响抗肿瘤治疗的重要因素.     

肿瘤相关中性粒细胞在肿瘤免疫治疗中的研究进展北大核心CSCD

肿瘤相关中性粒细胞(TANs)是浸润在肿瘤细胞周围的免疫细胞,在调节肿瘤的生长和侵袭方面发挥重要作用。在肿瘤微环境(TME)中TANs通过释放多种促炎、免疫调节和血管生成因子等,直接或间接地作用于肿瘤细胞来促进或抑制肿瘤的发生、进展和转移。同时TME内的多种细胞因子和趋化因子以及其他细胞的旁分泌信号又会负调控TANs的极化。TANs极化分为抗肿瘤的N1型和促肿瘤的N2型。随着对机体免疫功能研究的不断深入,发现TANs的极化调控具有高度的重编程性,在肿瘤免疫逃逸和免疫治疗中都起着非常重要的作用。靶向TANs极化的重编程开发肿瘤免疫治疗药物具有很强的可行性。本文将对TANs在肿瘤免疫中的研究进展进行综述。     

Tim-3与肿瘤免疫的研究进展

肿瘤是威胁人类健康的重要疾病,其治疗一直是医学领域的难点.近些年来,以抗体为代表的免疫治疗策略在肿瘤治疗的相关研究中显示出了极大的优势.Tim-3是Tim家族的重要成员,主要表达于辅助性T细胞(Th1)等多种免疫细胞中,其通过与配体的相互作用,可以调节靶细胞的功能状态,在抗感染免疫、自身免疫中均发挥着重要的免疫调控作用,而它在抗肿瘤免疫中的功能也逐渐受到重视.针对Tim-3的靶向干预有望成为肿瘤的免疫治疗中的新策略.     

肿瘤免疫代谢靶向治疗的研究进展

肿瘤免疫疗法的出现改变了许多肿瘤的治疗格局，是肿瘤治疗领域的重大突破。虽然其在一些肿瘤类型中显示出良好疗效，然而，总体反应率仍然偏低，因此需要开发新型的免疫治疗药物及治疗策略。代谢重编程是肿瘤细胞的一大特征，肿瘤微环境中免疫代谢的复杂性是影响肿瘤免疫治疗疗效的重要因素。近年来的研究表明，靶向免疫代谢可以减少免疫抑制，增强抗肿瘤免疫，提高现有肿瘤免疫疗法的疗效甚至克服耐药。文章综述了靶向肿瘤免疫代谢途径治疗的最新进展，包括靶向糖代谢、氨基酸代谢、核苷酸代谢和脂质代谢等，为开发免疫代谢靶向治疗潜力，寻找新靶点提供新思路。     

树突状细胞表达的PD-L1的研究进展

树突状细胞（DC）是专职的抗原提呈细胞,通过表达多种免疫调节分子在调节T细胞免疫反应中起关键作用。其表达的PD-L1是近年来新发现的B7家族的负性共刺激分子,与其相应受体结合,能够传递负性刺激信号导致T细胞反应无力,抑制细胞因子的分泌,诱导活化T细胞凋亡,最终诱导免疫耐受,介导肿瘤免疫逃逸,并在自身免疫性疾病,病毒,细菌感染等免疫反应中起重要作用。     

微环境中调节性T细胞与乳腺癌关系的研究进展

乳腺癌肿瘤免疫微环境是乳腺癌细胞与免疫细胞、免疫分子之间相互作用的场所,对乳腺癌的发生发展及预后产生重要影响.调节性T细胞(Tregs)作为一类具有免疫抑制功能的T淋巴细胞亚群,可通过抑制T细胞的功能,抑制机体抗肿瘤免疫,促进肿瘤的发生发展.研究显示,乳腺肿瘤免疫微环境中Tregs在乳腺癌发生、发展以及靶向治疗中发挥着重要作用.     

负性共刺激分子阻断抗体用于肿瘤治疗的研究进展北大核心CSCD

在免疫系统中,负性共刺激分子可通过受体-配体的结合而抑制免疫应答,避免免疫造成的组织损伤,在维持自身免疫耐受方面发挥重要作用。负性共刺激分子也参与调节肿瘤的发生发展,细胞毒性T细胞相关抗原4(CTLA-4)和程序性死亡分子1(PD-1)主要表达于活化的T细胞,它们与相应配体结合后可传递抑制性信号,从而抑制机体的抗肿瘤免疫,导致肿瘤免疫逃逸的发生。在肿瘤患者中,利用特异性的抗体阻断这些负性共刺激分子,可消除它们的免疫抑制功能,从而促进机体的抗肿瘤免疫应答,实现对肿瘤生长的有效抑制。现针对负性共刺激分子的阻断抗体在肿瘤治疗中的研究进展进行综述。     

Inhibitory receptors as targets for cancer immunotherapy

Inhibitory receptors expressed on T cells control immune responses while limiting autoimmunity. However, tumors can hijack these “checkpoints” for protection from immune attack. Tumor‐specific T cells that exhibit an exhausted, unresponsive phenotype express high levels of inhibitory receptors including CTLA4, PD1, and LAG3, among others. Intratumoral regulatory T cells promote immunosuppression and also express multiple inhibitory receptors. Overcoming this inhibitory receptor‐mediated immune tolerance has thus been a major focus of recent cancer immunotherapeutic developments. Here, we review how boosting the host's immune system by blocking inhibitory receptor signaling with antagonistic mAbs restores the capacity of T cells to drive durable antitumor immune responses. Clinical trials targeting the CTLA4 and PD1 pathways have shown durable effects in multiple tumor types. Many combinatorial therapies are currently being investigated with encouraging results that highlight enhanced antitumor immunogenicity and improved patient survival. Finally, we will discuss the ongoing identification and dissection of novel T‐cell inhibitory receptor pathways, which could lead to the development of new combinatorial therapeutic approaches.     

Immunomodulation in the treatment of haematological malignancies

Despite the continuous advances in immunology and cancer biology, haematological malignancies are often incurable. Conventional chemotherapy and radiation are efficacious for some lymphoma and leukaemia, however relapse and progressive disease often occurs. The evidence that the immune system can play an essential role in controlling cancer progression provide a basis for the development of active therapies, such as immunization, aimed to evoke or amplify a tumour-specific immune response. However, the inability of the patient’s own immune system to mount effective responses against tumour antigens is a major limit of vaccination approaches. The adoptive transfer of effectors of the adaptive immune system is an attractive strategy to circumvent the limitations of autologous immune responses. Donor lymphocyte infusion and the transfer of monoclonal antibodies (MoAbs) have been the first forms of adoptive therapy approved for clinical use and are still fundamental components of immunotherapy of haematological malignancies. Due to the continuous characterization of tumour-specific antigen, the development of tumour-tailored therapies that exploit the specificity of antibodies and T cell receptors (TCRs) is progressing rapidly. This review highlights the current advances in the field of adoptive immunotherapy of haematological malignancies, starting by elucidating the ongoing progress in passive transfer of MoAbs. We will also discuss recent advances in the adoptive transfer with tumour-specific high avidity T cells, which can be generated ex vivo by the transfer of gene constructs encoding single chain antibodies or TCRs, thus redirecting T cell specificity to selected tumour antigens. The ability to produce gene-modified T cells of desired specificity and defined functional activity may improve in the future T cell based immunotherapy of cancer.     

Metabolism, LXR/LXR ligands, and tumor immune escape

The mechanisms of tumor immune evasion have gained increasing interest among the tumor immunologists, because of their ability to suppress spontaneous and immunotherapy-elicited antitumor responses. Recent studies clearly show that the deletion of cells/molecules involved in tumor evasion is capable of restoring antitumor immune responses, ultimately leading to tumor rejection in mouse tumor models. These studies further support and strengthen the idea to target not only the cancer cell-intrinsic defects but also those affecting cells of the microenvironment, such as immune cells. The alterations of cancer cell metabolism are also emerging as important regulators of immune cell function, with particular emphasis on immune-escape mechanisms. Indeed, intermediate or final products of cancer cell metabolism may interfere with the function of immune cells infiltrating the tumor microenvironment. This review will focus on the role of cholesterol metabolism, with particular emphasis on the axis LXR/LXR ligands. This axis has been shown to affect DC migration to lymphoid organs, thus dampening the induction of successful antitumor responses. Finally, we will discuss whether this pathway may interfere with other immune cells infiltrating tumors and how to improve spontaneous and immunotherapy-based antitumor responses by counteracting this immune-escape mechanism.     

Present and future of immune checkpoint blockade: Monotherapy to adjuvant approaches

Immune regulation of aggressive tumor growth is often outpaced by tumor up-regulation of ligands that inhibit effector immune responses through the activation of immune checkpoints. A few of such checkpoints include programmed death-1 (PD-1), cytotoxic T lymphocyte associated antigen-4 (CTLA-4), lymphocyte activation gene-3, T-cell immunoglobulin and mucin protein-3, Glucocorticoid-induced TNFR family-related receptor (GITR), and killer cell immunoglobulin like receptor. With the exception of GITR, after binding to their respective ligands these checkpoints induce down-modulation of immune responses to prevent autoimmunity. However, such immune mechanisms are co-opted by tumors to allow rapid tumor cell proliferation. Pre-clinical studies in antibody blockade of PD-1 and CTLA-4 have led to promising augmentation of effector immune responses in murine tumor models, and human antibodies against PD-1 and CTLA-4 alone or in combination have demonstrated tumor regression in clinical trials. The development of immune checkpoint blockade as a potential future immunotherapy has led to increasing interest in combining treatment modalities. Combination checkpoint blockade with chemotherapy and radiation therapy has shown synergistic effects in pre-clinical and clinical studies, and combination checkpoint blockade with bacterial vaccine vectors have produced increased effector immune responses in pre-clinical models. The future of immune checkpoint blockade may be as a powerful adjuvant alongside the current standard of care.     

Mechanism of antitumor activity of a single-chain interleukin-12 IgG3 antibody fusion protein (mscIL-12.her2.IgG3).

We have constructed an antibody interleukin-12 (IL-12) fusion protein (mscIL-12.her2.IgG3) that demonstrates significant antitumor activity against the murine carcinoma CT26-expressing human HER2/neu. We now report that this antitumor activity is dose dependent and comparable to or better than recombinant murine IL-12 (rMuIL-12) using subcutaneous and metastatic models of disease. The antitumor activity of mscIL-12.her2.IgG3 is reduced in Rag2 knockout mice, suggesting that T cells play a role in tumor rejection. In SCID-beige mice, the antitumor activity is further reduced, suggesting that natural killer (NK) cells or macrophages or both are also important. The isotype of the antibody response to HER2/neu is consistent with a switch from a Th2 to a Th1 immune response and the infiltration of mononuclear cell in tumors from mice treated with mscIL-12.her2.IgG3. Immunohistochemistry reveals that mscIL-12.her2.IgG3 is antiangiogenic. Thus, the mechanism of the antitumor activity exhibited by mscIL-12.her2.IgG3 is highly complex and involves a combination of T and NK cell activity, a switch to a Th1 immune response, and antiantiogenic activity. This is the first study comparing the in vivo antitumor activity of an antibody-IL-12 fusion protein and free IL-12. Our results suggest that antibody-IL-12 fusion proteins may be useful for the treatment of human cancer.     

Immune checkpoint failures in inflammatory myopathies: An overview

Dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), immune mediated necrotizing myopathy (IMNM) and overlap myositis (OM) are classified as inflammatory myopathies (IM) with involvement of autoimmune features such as autoreactive lymphocytes and autoantibodies. Autoimmunity can be defined as a loss in self-tolerance and attack of autoantigens by the immune system. Self-tolerance is achieved by a group of immune mechanisms occurring in central and periphal lymphoid organs and tissues, called immune checkpoints, that work in synergy to protect the body from harmful immune reactions. Autoimmune disorders appear when immune checkpoints fail. In this review, the different immune checkpoint failures are discussed in DM, PM, IBM and IMNM. Exploring research contribution in each of these immune checkpoints might help to highlight research perspectives in the field and obtain a more complete picture of IM disease pathology.     

High‐dimensional single‐cell proteomics analysis identifies immune checkpoint signatures and therapeutic targets in ulcerative colitis

Immune checkpoints are regulators of immune cells and play key roles in the modulation of immune responses. The role of checkpoints in autoimmune disease is poorly understood but likely to be central since checkpoint inhibition during cancer treatment can cause autoimmunity. We generated a high‐dimensional single‐cell proteomics data set from PBMCs of healthy individuals and patients with ulcerative colitis (UC) by mass cytometry, enabling systems‐wide analyses of immune cell frequencies and cell type‐specific expression patterns of 12 immune checkpoints. Subtle but significant changes in immune cell frequencies and checkpoint expression were observed between UC patients on different treatment regimens and between patients and healthy controls. Most strikingly, UC patients showed a reduced number of peripheral NK‐cells and those cells showed an altered phenotype including increased TIGIT expression. Based on these results, we modulated NK‐cell function ex vivo through targeting of TIGIT pathway members. In summary, we describe a pattern of changes in immune cell abundance and checkpoint expression as a basis for UC patient stratification and we show modulation of a corresponding immune cell subset through checkpoint targeting. Our approach can be used for the identification of pathogenic immune cell subsets and guide target selection in autoimmunity and chronic inflammation.     

The effect of class II gene transfection on the tumourigenicity of the H-2K-negative mouse leukaemia cell line K36.16

There is much evidence to suggest that potentially immunogenic tumour cells can escape cytolytic immune destruction by loss of class I antigen expression. Many tumours are allele-specific class I negative and, in murine systems, reconstitution of class I expression by gene transfection leads to an increase in tumour immunogenicity. In many systems where mice have rejected class I transfected tumour cells they are also immune to a subsequent challenge with the untransfected parent tumour. In this study we have examined the effect of stable class II antigen expression (induced by gene transfection) on a class I loss mutant (H-2Kk negative) murine cell line, K36.16. We show that H-2Ek expression is more effective at increasing tumour immunogenicity than the reconstitution of H-2Kk expression in these cells. This suggests that the induction of class II antigen expression on tumour cells may provide an effective way of enhancing tumour-specific immune responses in vivo.