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Immunometabolism: a new dimension in immunotherapy resistance

《医学前沿（英文）》 2023年第17卷第4期页码 585-616 doi: 10.1007/s11684-023-1012-z

摘要： Immune checkpoint inhibitors (ICIs) have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment, while substantial patients remain unresponsive or develop resistance to ICIs as a single agent, which is traceable to cellular metabolic dysfunction. Although dysregulated metabolism has long been adjudged as a hallmark of tumor, it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes. Correspondingly, people used to pay more attention to the effect of tumor cell metabolism on immunocytes, but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation, which opens up a whole new frontier called immunometabolism. The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy, whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response. Herein, we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes, and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance.

关键词： immune cell immunometabolism metabolic reprogramming immunotherapy resistance tumor microenvironment immune checkpoint inhibitor

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Developing effective tumor vaccines: basis, challenges and perspectives

XU Qingwen, CHEN Weifeng

《医学前沿（英文）》 2007年第1卷第1期页码 11-19 doi: 10.1007/s11684-007-0003-9

摘要： A remarkable advance in tumor immunology during the last decade is the elucidation of the antigenic basis of tumor recognition and destruction. A variety of tumor antigens have been identified using several strategies including conventional experiments and newly developed bioinformatics. Among these antigens, cancer/testis antigen (CT antigen) is considered to be the most promising target for immunotherapy by vaccination. Successful immunotherapy of tumors requires understanding of the natural relationship between the immune system and tumor in the status of differentiation, invasion and maturation. Continued progress in development of effective cancer vaccines depends on the identification of appropriate target antigens, the establishment of optimal immunization strategies without harmful autoimmune responses and the ability of manipulating tumor microenvironment to circumvent immune suppression and to augment the anti-tumor immune response.

关键词： development conventional identification elucidation Successful immunotherapy

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Natural killer cell lines in tumor immunotherapy

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《医学前沿（英文）》 2012年第6卷第1期页码 56-66 doi: 10.1007/s11684-012-0177-7

摘要：

Natural killer (NK) cells are considered to be critical players in anticancer immunity. However, cancers are able to develop mechanisms to escape NK cell attack or to induce defective NK cells. Current NK cell-based cancer immunotherapy is aimed at overcoming NK cell paralysis through several potential approaches, including activating autologous NK cells, expanding allogeneic NK cells, usage of stable allogeneic NK cell lines and genetically modifying fresh NK cells or NK cell lines. The stable allogeneic NK cell line approach is more practical for quality-control and large-scale production. Additionally, genetically modifying NK cell lines by increasing their expression of cytokines and engineering chimeric tumor antigen receptors could improve their specificity and cytotoxicity. In this review, NK cells in tumor immunotherapy are discussed, and a list of therapeutic NK cell lines currently undergoing preclinical and clinical trials of several kinds of tumors are reviewed.

关键词： natural killer cell natural killer cell line tumor immunotherapy genetic modification

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Nanovaccines for remodeling the suppressive tumor microenvironment: New horizons in cancer immunotherapy

Kai Shi, Matthew Haynes, Leaf Huang

《化学科学与工程前沿（英文）》 2017年第11卷第4期页码 676-684 doi: 10.1007/s11705-017-1640-4

摘要： Despite limited successes in clinical development, therapeutic cancer vaccines have experienced resurgence in recent years due to an enhanced emphasis upon co-mitigating factors underlying immune response. Specifically, reversing the immune-suppressive effects of the tumor microenvironment, mediated by a variety of cellular and molecular signaling mechanisms, has become fundamental toward enhancing therapeutic efficacy. Therein, our lab has implemented various nano-vaccines based on the lipid-coated calcium phosphate platform for combined immunotherapy, in which antigenic, epitope-associated peptides as well as immune-suppression inhibitors can be co-delivered, often functioning through the same formulation. In probing the mechanism of action of such systems and , an improved effect synergy can be elucidated, inspiring future preclinical efforts and hope for clinical success.

关键词： vaccine nanoparticle tumor immunotherapy microenvironment

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Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma

《医学前沿（英文）》 2023年第17卷第4期页码 699-713 doi: 10.1007/s11684-022-0972-8

摘要： Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has achieved 40%–50% long-term complete response in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients. However, the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation. A multi-center phase I/II trial of anti-CD19 CD28z CAR-T (FKC876, ChiCTR1800019661) was conducted. Among 22 evaluable DLBCL patients, seven achieved complete remission, 10 experienced partial remissions, while four had stable disease by day 29. Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients, and compared at different stages of treatment. M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells, leading to CAR-T cell therapy failure and disease progression in DLBCL. Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy, during both cell expansion and disease progression, which could not be altered by infiltrating CAR-T cells. Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments. Thus, our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.

关键词： anti-CD19 chimeric antigen receptor T immunotherapy diffuse large B cell lymphoma tumor microenvironment tumor-associated macrophage metabolism

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-1BBL expressed by eukaryotic cells activates immune cells and suppresses the progression of murine tumor

Hui QIU, Hui ZHANG, Zuohua FENG

《医学前沿（英文）》 2009年第3卷第1期页码 20-25 doi: 10.1007/s11684-009-0006-9

摘要： The interaction by co-stimulatory molecules 4-1BB and 4-1BB ligand (4-1BBL) plays an important role in the activation, proliferation and differentiation of T lymphocytes. The function of 4-1BB/4-1BBL expressed by the immune cells has been the focus for many tumor immunotherapy efforts. In this study, 4-1BBL was expressed in non-immune cells and non-tumor cells, and the role of 4-1BBL in lymphocyte activation and tumor suppression was investigated. The plasmid p4-1BBL containing the full length of mouse 4-1BBL cDNA sequence was constructed, and the plasmid was transfected into baby hamster kidney (BHK) cells and murine muscle cells by means of lipofectin-mediated or naked plasmid DNA injection into the muscle directly. The study demonstrated that the molecule 4-1BBL expressed by BHK cells could enhance the proliferation and cytotoxicity of lymphocytes, and it could increase the expression level of IL-2 and IFN-γ. The treatment with plasmid p4-1BBL revealed that the number of CD8 T cells in the peri-tumoral tissue increased markedly, and the growth rate of the tumor was significantly lower than that of control group. These findings suggest that expression of 4-1BBL by normal cells in the tumor microenvironment can enhance the proliferation and other functions of T lymphocytes. This therapeutic method may provide a promising approach for tumor immunotherapy.

关键词： 4-1BB ligand tumor immunotherapy tumor microenvironment

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Translational medicine in hepatocellular carcinoma

null

《医学前沿（英文）》 2012年第6卷第2期页码 122-133 doi: 10.1007/s11684-012-0193-7

摘要：

Hepatocellular carcinoma (HCC) is a highly complex disease that is generally resistant to commonly used chemotherapy and radiotherapy. Consequently, there is an urgent need for the development of new treatment strategies for this devastating disease. In the past decade, tremendous progress has been achieved in the molecular stratification of HCCs for diagnosis, prognosis, and therapeutic decision-making. To date, the molecular classification of HCCs has been carried out through transcriptomic, genetic and epigenetic profiling of tumors. Such research has led to identification of several potential molecular targets in HCC, and subsequently, development of novel systemic agents for the treatment of HCC has begun in earnest. In this article, we review the current knowledge of the molecular pathogenesis of HCC and outline potential areas for application of this knowledge in a clinical setting. As a typical virus and inflammation-associated cancer, both host immune response and tumor microenvironment have crucial roles in HCC pathogenesis. In addition, we examine the potential of immunotherapy and strategies targeting various components of the tumor microenvironment, as well as novel molecular and cellular targets in HCC such as cancer stem cells.

关键词： hepatocellular carcinoma molecular classification molecular targeted therapies tumor microenvironment immunotherapy

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CAR T cells redirected against tumor-specific antigen glycoforms: can low-sugar antigens guarantee a

《医学前沿（英文）》 2022年第16卷第3期页码 322-338 doi: 10.1007/s11684-021-0901-2

摘要： Immune-based therapies have experienced a pronounced breakthrough in the past decades as they acquired multiple US Food and Drug Administration (FDA) approvals for various indications. To date, six chimeric antigen receptor T cell (CAR-T) therapies have been permitted for the treatment of certain patients with relapsed/refractory hematologic malignancies. However, several clinical trials of solid tumor CAR-T therapies were prematurely terminated, or they reported life-threatening treatment-related damages to healthy tissues. The simultaneous expression of target antigens by healthy organs and tumor cells is partly responsible for such toxicities. Alongside targeting tumor-specific antigens, targeting the aberrantly glycosylated glycoforms of tumor-associated antigens can also minimize the off-tumor effects of CAR-T therapies. Tn, T, and sialyl-Tn antigens have been reported to be involved in tumor progression and metastasis, and their expression results from the dysregulation of a series of glycosyltransferases and the endoplasmic reticulum protein chaperone, Cosmc. Moreover, these glycoforms have been associated with various types of cancers, including prostate, breast, colon, gastric, and lung cancers. Here, we discuss how underglycosylated antigens emerge and then detail the latest advances in the development of CAR-T-based immunotherapies that target some of such antigens.

关键词： cancer immunotherapy chimeric antigen receptor solid tumors tumor-associated antigen glycosylation O-glycans adoptive cell therapy

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Analysis of interactions of immune checkpoint inhibitors with antibiotics in cancer therapy

《医学前沿（英文）》 2022年第16卷第3期页码 307-321 doi: 10.1007/s11684-022-0927-0

摘要： The discovery of immune checkpoint inhibitors, such as PD-1/PD-L1 and CTLA-4, has played an important role in the development of cancer immunotherapy. However, immune-related adverse events often occur because of the enhanced immune response enabled by these agents. Antibiotics are widely applied in clinical treatment, and they are inevitably used in combination with immune checkpoint inhibitors. Clinical practice has revealed that antibiotics can weaken the therapeutic response to immune checkpoint inhibitors. Studies have shown that the gut microbiota is essential for the interaction between immune checkpoint inhibitors and antibiotics, although the exact mechanisms remain unclear. This review focuses on the interactions between immune checkpoint inhibitors and antibiotics, with an in-depth discussion about the mechanisms and therapeutic potential of modulating gut microbiota, as well as other new combination strategies.

关键词： tumor immunotherapy immune checkpoint inhibitor antibiotics gut microbiota drug–drug interaction

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医学科技颠覆性技术展望

李永洁,杨俊涛,杜建

《中国工程科学》 2018年第20卷第6期页码 64-68 doi: 10.15302/J-SSCAE-2018.06.010

摘要：

随着医学与现代信息技术、材料科技等技术的深度交叉融合，极大地促进了医学科技的发展，疾病诊断和治疗模式发生革命性的变化。本文主要从医学领域的肿瘤免疫治疗、基因编辑技术、医学人工智能、合成生物学技术和干细胞与转化医学五个技术方向，分析评价其发展态势；结合文献、智库报告和专家观点，对医学科技发展方向进行初探，提出重视医学基础研究投入、优化医学科技战略顶层设计、完善政策及监管体系等政策建议。

关键词：医学科技颠覆性技术肿瘤免疫治疗基因编辑

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Prospects of immunotherapy for cancer

Zhinan Chen

《医学前沿（英文）》 2019年第13卷第1期页码 1-2 doi: 10.1007/s11684-019-0691-y

摘要：

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Chimeric antigen receptor T cell targeting EGFRvIII for metastatic lung cancer therapy

Zhao Zhang, Jun Jiang, Xiaodong Wu, Mengyao Zhang, Dan Luo, Renyu Zhang, Shiyou Li, Youwen He, Huijie Bian, Zhinan Chen

《医学前沿（英文）》 2019年第13卷第1期页码 57-68 doi: 10.1007/s11684-019-0683-y

摘要：

Lung cancer is the most common incident cancer and the leading cause of cancer death. In recent years, the development of tumor immunotherapy especially chimeric antigen receptor T (CAR-T) cell has shown a promising future. Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation expressed in various types of tumors and has been detected in non-small cell lung cancer with a mutation rate of 10%. Thus, EGFRvIII is a potential antigen for targeted lung cancer therapy. In this study, CAR vectors were constructed and transfected into virus-packaging cells. Then, activated T cells were infected with retrovirus harvested from stable virus-producing single clone cell lines. CAR expression on the surfaces of the T cells was detected by flow cytometry and Western blot. The function of CAR-T targeting EGFRvIII was then evaluated. The EGFRvIII-CAR vector was successfully constructed and confirmed by DNA sequencing. A stable virus-producing cell line was produced from a single clone by limited dilution. The culture conditions for the cell line, including cell density, temperature, and culture medium were optimized. After infection with retrovirus, CAR was expressed on more than 90% of the T cells. The proliferation of CAR-T cells were induced by cytokine and specific antigen in vitro. More importantly, EGFRvIII-CART specifically and efficiently recognized and killed A549-EGFRvIII cells with an effector/target ratio of 10:1 by expressing and releasing cytokines, including perforin, granzyme B, IFN-g, and TNF-α. The in vivo study indicated that the metastasis of A549-EGFRvIII cells in mice were inhibited by EGFRvIII-CART cells, and the survival of the mice was significantly prolonged with no serious side effects. EGFRvIII-CART showed significantly efficient antitumor activity against lung cancer cells expressing EGFRvIII in vivo and in vitro. Therefore, CAR-T targeting EGFRvIII is a potential therapeutic strategy in preventing recurrence and metastasis of lung cancer after surgery.

关键词： chimeric antigen receptor T cells epidermal growth factor receptor lung cancer immunotherapy tumor immunology

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Dendritic cell vaccines in cancer immunotherapy: from biology to translational medicine

Hongmei Xu, Xuetao Cao

《医学前沿（英文）》 2011年第5卷第4期页码 323-332 doi: 10.1007/s11684-011-0172-4

摘要：

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Heterogeneity of the tumor immune microenvironment and clinical interventions

《医学前沿（英文）》 2023年第17卷第4期页码 617-648 doi: 10.1007/s11684-023-1015-9

摘要： Heterogeneity of the tumor immune microenvironment and clinical interventions

关键词： Heterogeneity tumor immune

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Challenges of NK cell-based immunotherapy in the new era

null

《医学前沿（英文）》 2018年第12卷第4期页码 440-450 doi: tzg@ustc.edu.cn

摘要：

Natural killer cells (NKs) have a great potential for cancer immunotherapy because they can rapidly and directly kill transformed cells in the absence of antigen presensitization. Various cellular sources, including peripheral blood mononuclear cells (PBMCs), stem cells, and NK cell lines, have been used for producing NK cells. In particular, NK cells that expanded from allogeneic PBMCs exhibit better efficacy than those that did not. However, considering the safety, activities, and reliability of the cell products, researchers must develop an optimal protocol for producing NK cells from PBMCs in the manufacture setting and clinical therapeutic regimen. In this review, the challenges on NK cell-based therapeutic approaches and clinical outcomes are discussed.

关键词： natural killer cells immunotherapy adoptive transfer genetic modification immune checkpoint inhibitor