2018年肿瘤免疫研究热点回眸

 肿瘤免疫疗法已成为肿瘤治疗的重要手段，是肿瘤研究领域的焦点和热点。肿瘤免疫治疗相关药物相继问世，而2018年度诺贝尔生理学或医学奖授予两位在肿瘤免疫治疗中有突出贡献的免疫学家，更是确立了肿瘤免疫治疗时代的到来。本文概述了2018年肿瘤免疫治疗研究的热点及进展，包括新的肿瘤免疫检查点的发现、T细胞耗竭的深入探究、新的肿瘤免疫抑制细胞亚群的发现以及肿瘤免疫治疗新策略的探索。     

2022年肿瘤免疫研究热点回眸

肿瘤免疫治疗已成为继手术、放疗、化疗之后的第四类肿瘤治疗方法，为当今国际研究的热点领域。在肿瘤免疫治疗新时代，以免疫检查点抑制剂、基因工程化修饰免疫细胞为代表的免疫疗法被认为具有广阔前景。概述了2022年肿瘤免疫治疗领域研究的热点及关键进展，包括嵌合抗原受体T细胞（CAR-T）在实体瘤治疗中的突破、维持记忆性T细胞生存和功能新机制的发现、改善肿瘤免疫抑制微环境提高免疫治疗疗效的深入探究以及瘤内微生物对抗肿瘤免疫反应的重要影响作用。     

光动力疗法诱导的免疫原性细胞死亡的研究进展

光动力疗法（PDT）已被证明可以诱导免疫原性细胞死亡（ICD）.但是由于PDT本身的局限性以及肿瘤部位的免疫原性差和免疫抑制环境的原因，单独的PDT在癌症免疫治疗中难以获得强大而持久的适应性抗肿瘤功效，往往需要采用不同的策略来提高肿瘤的免疫应答效果.因此，文章简述了光动力学机理、ICD原理，以及对PDT诱导的ICD的各种不同策略进行了总结和讨论，策略包括增加氧气（O₂）和靶向性提高PDT效果，PDT联合光热疗法（PTT）和化疗等治疗方式，PDT结合免疫检查点以及免疫佐剂抑制来提高ICD效应，以此为研究人员提供更多的癌症免疫治疗方面的参考.     

肿瘤抗原在免疫治疗中的应用

介绍肿瘤抗原分类、肿瘤细胞逃逸机体免疫监制的机制、机体抗肿瘤的免疫学机制和肿瘤抗原在免疫治疗中的应用。随着分子生物学的发展,肿瘤抗原在肿瘤免疫治疗方面将发挥重要的作用。     

肿瘤免疫:肿瘤治疗的新希望

 随着肿瘤学、免疫学及分子生物学等相关学科的迅速发展和交叉渗透,肿瘤免疫治疗技术突飞猛进,成为肿瘤治疗新的热点。肿瘤免疫治疗是应用免疫学原理和方法,提高肿瘤细胞的免疫原性和对效应细胞杀伤的敏感性,激发和增强机体抗肿瘤免疫应答,并应用免疫细胞和效应分子输注宿主体内,协同机体免疫系统杀伤肿瘤、抑制肿瘤生长。在某些肿瘤,如黑色素瘤、非小细胞肺癌等,免疫治疗展现出强大的抗肿瘤活性,部分免疫治疗药物已经获得美国FDA批准。2013年《Science》杂志将肿瘤的免疫治疗评为年度最重要的科学突破。免疫治疗成为继手术、放射治疗和化学治疗之后又一种重要的抗肿瘤治疗手段,成为攻克恶性肿瘤的希望。本文综述肿瘤免疫学的历史、发展规律、未来方向及中国的肿瘤免疫发展情况。     

基于基因表达谱预测肿瘤浸润免疫细胞类型及比例的解卷积算法

肿瘤浸润免疫细胞通过发挥促肿瘤和抗肿瘤的作用,可以深刻地影响肿瘤的进展以及抗癌治疗的成功.因此,对于肿瘤浸润免疫细胞的量化有望揭示免疫系统在人类癌症中的多方面作用及其参与肿瘤逃逸机制和对治疗的反应.解卷积的目的就是试图在复杂组织里存在的免疫细胞中寻找新的免疫疗法,其核心思想是利用算法和免疫细胞的表达特征,从细胞混合物的表达数据中量化免疫细胞比例信息,以准确刻画肿瘤样本测序数据的免疫浸润情况.为此,提出了一个新的基于逐步回归策略的解卷积算法模型,并使用真实的肿瘤样本微阵列数据和RNA-Seq测序数据来测试该算法的准确性.与CIBERSORT和dtangle相比较,具有良好的解卷积性能.     

Development of a nano-immunomodulator encapsulating R837 and caffeine for combined radio-/immunotherapy against orthotopic breast cancer

Immunotherapy is an ascendant approach in cancer treatment. It shows more pronounced effects on killing cancer cells in a specific manner in particular against metastasis more than traditional techniques, such as chemotherapy or surgery. However, tumor immunosuppression limits the response of the immune system to cancer development. In this study, we developed a lipid-based nanocarrier doubly loaded with imiquimod (R837), a toll-like receptor 7 agonist, and caffeine, an adenosine receptor antagonist. This R837/caffeine loaded nanocarrier served as a nano-immunomodulator (RC-nIM) for combination treatment with radiotherapy (RT) against orthotopic breast cancer. RT-induced immunogenic cell death facilitated the production of tumor antigen and elicited the immune response in corporation with R837-medaited activation of antigen-presenting cells (APCs) while RC-nIMs being adopted. Additionally, caffeine, an adenosine analog, can successfully compete with adenosine in the tumor. The tumor-bearing mice that received RT together with RC-nIMs experienced the best antitumor effects and exhibited higher levels of T cells and APCs within the tumor; the growth of secondary tumors was also limited. This work serves as a proof-of-concept study for the development of a new immunotherapy strategy against cancer.     

RH株弓形虫抗原及高效价多克隆抗体的制备

通过制备和分析弓形虫抗原蛋白，并以此抗原制备高效价的兔抗弓形虫多克隆抗体，为弓形虫的免疫检测和诊断提供有效的方法和途径，同时也为基因工程产物的鉴定提供方便有效的检测手段．速殖子主要来源于感染后72～74h获得的腹水，通过常规方法制备和提纯弓形虫可溶性抗原，采用SDS-AGE方法分析抗原蛋白的分子量．以抗原和福氏佐剂制备成完全和不完全福氏佐剂通过脊柱两旁皮下多点免疫的途径免疫新西兰大白兔，制备兔抗弓形体多克隆抗体，间接ELISA法检测血清中抗体的效价．经过观察所获得的虫体阶段主要处在宿主细胞巨噬细胞内而尚未逸出阶段，通过对结果的分析，所制备的弓形体抗原的分子量主要集中在17～156ku之间，与文献报道有差异，兔抗弓形体抗体效价在60000以上．该研究结果将为弓形体的蛋白质研究，免疫诊断、预防及有效治疗奠定基础．     

Tumor carbohydrate antigens and strategies to develop cancer vaccines and drugs

Certain carbohydrate antigens of malignantly transformed cells have been identified as markers for the onset of cancer and have become targets for the development of anticancer vaccine therapies. For tumor antigens, many carbohydrate antigens belong to T-independent (TI) antigens. Carbohydrate conjugated to protein carriers can switch TI antigen to a T-dependent (TD) antigen. Attempts to add an innate immune response element (such as Toll-like receptor ligand) to carbohydrate TI-antigens have also been studied. Glycosylation inhibitors or small interfering RNA have also been used for antitumor and/or antiviral agents. This review aims at describing the vast spectrum of tumor carbohydrate antigens and strategies to develop cancer vaccines and drugs.     

白细胞介素-2(IL-2)在兽医中的应用进展(综述)

白细胞介素-2(IL-2)是动物机体最重要的细胞因子之一,在抗感染、抗肿瘤、抗毒索和免疫调节中发挥重要作用,而成为当今免疫学、临床医学等领域的研究热点。主要就IL-2在兽医中作为免疫佐剂和免疫治疗剂的应用进展进行综述。     

脉冲输注IL-2与免疫效应细胞的肿瘤免疫治疗动力学分析

本文研究一类具脉冲输注方式的肿瘤免疫治疗三维脉冲微分方程模型.运用频闪映射、Floquet乘子理论及脉冲比较定理等分析方法,研究模型周期解的存在性和渐近稳定性,从而获得肿瘤灭绝的条件.通过数值模拟验证了所获理论结果的正确性.     

POLE/POLD1突变与肿瘤免疫治疗研究进展

 阐述了DNA聚合酶ε（polymerase epsilon，POLE）和DNA聚合酶delta 1（polymerase delta 1，POLD1）基因编码的亚基参与DNA复制和校对，总结了POLE/POLD1突变对肿瘤突变负荷以及肿瘤内免疫细胞浸润的影响，综述了POLE/POLD1突变在子宫内膜癌、结直肠癌、肺癌中的研究进展，并讨论了POLE/POLD1突变作为潜在的免疫检查点抑制剂疗效预测分子标志物面临的诸多挑战。     

Prophylactic cancer vaccine,from concept to reality？

The demonstration that for infectious diseasesvaccine-induced immunity is in principle only effectivebefore rather than after infection occurs, provides valuableinsights in understanding the nature of immune system andthe challenges in cancer treatment. Besides the alreadyknown underlying counter-back mechanisms, the astro-nomical numbers of tumor cells in established tumorscould overwhelm the limited amount of specific T cellsinduced by vaccination, which may account for the modestefficiency of immunotherapy against cancer. We speculatethat the long window period for cancer development willallow immune-intervening strategies （e.g., the proper pro-phylactic vaccination） to promote adaptive mechanismstoward an enhanced immunosurveillance, which couldeffectively eradicate or at least control the few precancer-ous cells undergoing neoplastic transformation during earlypremalignant stages in cancer development, and protect thehost from lethal tumor formation. It should be emphasizedthat the pre-cancer-associated antigens but not the tumor-associated antigens seem to be the suitable antigens fordesigning prophylactic cancer vaccines. In addition, anideal prophylactic cancer vaccine may contain multiplepre-cancer-associated antigens, which will provide broadand effective immune protection in a heterogeneous humanpopulation. Finally, we demonstrated that placenta-derivedgp96, which can be readily obtained in high amount forvaccination, has the ability to initiate antitumor T-cellimmunity via association with multiple embryo-cancerantigens. Further understanding placental gp96 associatedwith carcinoembryonic antigen repertoires that orchestrateimmune defense networks against cancer formation willallow to provide an effective prophylactic approach incancer prevention.     

Response to self antigen imprints regulatory memory in tissues

Immune homeostasis in tissues is achieved through a delicate balance between pathogenic T-cell responses directed at tissue-specific antigens and the ability of the tissue to inhibit these responses. The mechanisms by which tissues and the immune system communicate to establish and maintain immune homeostasis are currently unknown. Clinical evidence suggests that chronic or repeated exposure to self antigen within tissues leads to an attenuation of pathological autoimmune responses, possibly as a means to mitigate inflammatory damage and preserve function. Many human organ-specific autoimmune diseases are characterized by the initial presentation of the disease being the most severe, with subsequent flares being of lesser severity and duration. In fact, these diseases often spontaneously resolve, despite persistent tissue autoantigen expression. In the practice of antigen-specific immunotherapy, allergens or self antigens are repeatedly injected in the skin, with a diminution of the inflammatory response occurring after each successive exposure. Although these findings indicate that tissues acquire the ability to attenuate autoimmune reactions upon repeated responses to antigens, the mechanism by which this occurs is unknown. Here we show that upon expression of self antigen in a peripheral tissue, thymus-derived regulatory T cells (T(reg) cells) become activated, proliferate and differentiate into more potent suppressors, which mediate resolution of organ-specific autoimmunity in mice. After resolution of the inflammatory response, activated T(reg) cells are maintained in the target tissue and are primed to attenuate subsequent autoimmune reactions when antigen is re-expressed. Thus, T(reg) cells function to confer 'regulatory memory' to the target tissue. These findings provide a framework for understanding how T(reg) cells respond when exposed to self antigen in peripheral tissues and offer mechanistic insight into how tissues regulate autoimmunity.     

The growth dynamics of tumor subject to both immune surveillance and external therapy intervention

Considering the growth of tumor cells modeled by an enzyme dynamic process under an immune surveillance, we studied in anti-tumor immunotherapy the single-variable growth dynamics of tumor cells subject to a multiplicative noise and an external therapy intervention simultaneously. The law of tumor growth of the above anti-tumor immunotherapy model was revealed through numerical simula- tions to the relevant stochastic dynamic differential equation. Two simulative parameters of therapy, i.e., therapy intensity and therapy duty-cycle, were introduced to characterize a treatment process similar to a tumor clinic therapy. There exists a critical therapy boundary which, in an expo- nent-decaying form, divides the parameter region of therapy into an invalid and a valid treatment zone, respectively. A greater critical therapy duty-cycle is necessary to achieve a valid treatment for a lower therapy intensity while the critical therapy intensity decreases accordingly with an enhancing immunity. A primary clinic observation of the patients with the typical non-hodgekin’s lymphoma was carried out, and there appears a basic agreement between clinic observations and dynamic simulations.     

肿瘤生物免疫治疗研究进展

 肿瘤免疫编辑理论的提出阐述了免疫系统在肿瘤发生发展中不可忽视的作用。靶向肿瘤免疫负调控的单克隆抗体在临床的成功应用,更确定了调控免疫系统对有效治疗肿瘤的重要性。未来大有发展潜力的联合免疫治疗手段主要有抗体、细胞因子、肿瘤疫苗、过继免疫细胞治疗和溶瘤病毒等。免疫治疗联合传统的肿瘤治疗包括手术、放疗和化疗,是今后提高肿瘤治疗效果的重要研究和应用方向。本文主要综述抗体治疗、肿瘤疫苗治疗、细胞过继免疫治疗、溶瘤病毒治疗的研究进展,提出相关研究中存在的问题,并对其进行展望。     

Advances in researches on the immune dysregulation and therapy of severe acute pancreatitis

During the development and progression of severe acute pancreatitis (SAP), conspicuous immune dysregulation develops, which is mainly manifested as excessive immune response in the early stage and immunosuppression in the late stage. This process involves complex changes in a variety of immune molecules and cells, such as cytokines, complements, lymphocytes, and leukocytes. With the gradual deepening of studies on the development and progression of SAP, the role of immune dysregulation in the pathogenesis of SAP has attracted more and more attention. In this article, we review the advances in research on the immune dysregulation in SAP and the immunotherapy of this disease through exploring the formation of excessive immune response and immune suppression as well as their mutual transformation.     

Therapy of tuberculosis in mice by DNA vaccination.

Mycobacterium tuberculosis continues to kill about 3 million people every year, more than any other single infectious agent. This is attributed primarily to an inadequate immune response towards infecting bacteria, which suffer growth inhibition rather than death and subsequently multiply catastrophically. Although the bacillus Calmette-Guerin (BCG) vaccine is widely used, it has major limitations as a preventative measure. In addition, effective treatment requires that patients take large doses of antibacterial drug combinations for at least 6 months after diagnosis, which is difficult to achieve in many parts of the world and is further restricted by the emergence of multidrug-resistant strains of M. tuberculosis. In these circumstances, immunotherapy to boost the efficiency of the immune system in infected patients could be a valuable adjunct to antibacterial chemotherapy. Here we show in mice that DNA vaccines, initially designed to prevent infection, can also have a pronounced therapeutic action. In heavily infected mice, DNA vaccinations can switch the immune response from one that is relatively inefficient and gives bacterial stasis to one that kills bacteria. Application of such immunotherapy in conjunction with conventional chemotherapeutic antibacterial drugs might result in faster or more certain cure of the disease in humans.     

Expression of tumour-specific antigens underlies cancer immunoediting

Cancer immunoediting is a process by which immune cells, particularly lymphocytes of the adaptive immune system, protect the host from the development of cancer and alter tumour progression by driving the outgrowth of tumour cells with decreased sensitivity to immune attack. Carcinogen-induced mouse models of cancer have shown that primary tumour susceptibility is thereby enhanced in immune-compromised mice, whereas the capacity for such tumours to grow after transplantation into wild-type mice is reduced. However, many questions about the process of cancer immunoediting remain unanswered, in part because of the known antigenic complexity and heterogeneity of carcinogen-induced tumours. Here we adapted a genetically engineered, autochthonous mouse model of sarcomagenesis to investigate the process of cancer immunoediting. This system allows us to monitor the onset and growth of immunogenic and non-immunogenic tumours induced in situ that harbour identical genetic and histopathological characteristics. By comparing the development of such tumours in immune-competent mice with their development in mice with broad immunodeficiency or specific antigenic tolerance, we show that recognition of tumour-specific antigens by lymphocytes is critical for immunoediting against sarcomas. Furthermore, primary sarcomas were edited to become less immunogenic through the selective outgrowth of cells that were able to escape T lymphocyte attack. Loss of tumour antigen expression or presentation on major histocompatibility complex I was necessary and sufficient for this immunoediting process to occur. These results highlight the importance of tumour-specific-antigen expression in immune surveillance, and potentially, immunotherapy.