Targeting immune-checkpoint inhibitor resistance mechanisms by MEK inhibitor and agonist anti-CD40 antibody combination therapy.

IF 4.1 Q2 CELL BIOLOGY

Cell Stress Pub Date : 2020-08-06 DOI:10.15698/cst2020.10.233

Daniel Baumann, Rienk Offringa

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引用次数: 3

Abstract

The widespread application of immune-checkpoint blockade (ICB) has resulted in unprecedented response rates in patients with immunogenic cancers, such as melanoma and lung cancer. However, sub-groups of patients with these indications do not respond to ICB, and the same applies to patients with other cancer types. Mechanisms of resistance to ICB include low tumor immunogenicity associated with low T cell infiltration ('cold' tumors), suppression of anti-tumor immunity by immunosuppressive cells in the tumor microenvironment (TME), lack of antigen-presentation and immune escape (e.g. by downregulation of MHC-I on tumor cells) as well as oncologic pathways that suppress immune responses. Combination strategies, involving cytostatic drugs, harbor the potential to overcome refractoriness to immunotherapy. However, suppression of immune cell function by cytostatic drugs may limit the efficacy. In our study, we show that combination treatment of targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) and agonist immunostimulatory anti-CD40 antibody (Ab) is particularly suitable in counteracting aforementioned ICB resistance mechanisms (Fig. 1).

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靶向免疫检查点抑制剂MEK抑制剂与激动剂抗cd40抗体联合治疗的耐药机制。

免疫检查点阻断(ICB)的广泛应用在免疫原性癌症(如黑色素瘤和肺癌)患者中产生了前所未有的应答率。然而，具有这些适应症的患者亚组对ICB没有反应，这同样适用于其他癌症类型的患者。对ICB的耐药机制包括与低T细胞浸润(“冷”肿瘤)相关的低肿瘤免疫原性，肿瘤微环境(TME)中免疫抑制细胞对抗肿瘤免疫的抑制，缺乏抗原呈递和免疫逃逸(例如通过肿瘤细胞上MHC-I的下调)以及抑制免疫反应的肿瘤途径。包括细胞抑制药物在内的联合治疗策略，有可能克服免疫治疗的难治性。然而，细胞抑制药物对免疫细胞功能的抑制可能会限制其疗效。在我们的研究中，我们发现靶向抑制丝裂原活化蛋白激酶(MAPK)激酶(MEK)和激动剂免疫刺激抗cd40抗体(Ab)的联合治疗特别适合对抗上述ICB耐药机制(图1)。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)

CiteScore

13.50

自引率

0.00%

发文量

审稿时长

15 weeks

期刊介绍： Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.