ICAM-1 Is Overexpressed by Cancers and Negatively Impacts Antibody-Based Therapies Including Antibody–Drug Conjugates

IF 4.5 3区 医学 Q2 IMMUNOLOGY
J. Bradford Kline, Luigi Grasso, Nicholas C. Nicolaides
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Abstract

Humoral immunity utilizes antibodies and immune effector cells to mediate dysregulated cancer cell killing. These mechanisms are referred to as Humoral Immuno-Oncology (HIO). HIO immunosuppression is mediated by tumor-produced proteins called HIO factors. Using a combination of patient serum analysis and literature searches, we screened a number of samples to determine if they suppressed HIO. Herein, we identified that ICAM-1 (intercellular adhesion molecule 1) can bind IgG1-type antibodies and suppress their immune effector activity. Through a series of mutagenesis, we identified a unique motif within the IgG1CH3 domain essential for ICAM-1 binding, which inhibits antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Conservative amino acid substitutions within the CH3 domain were able to abrogate ICAM-1 binding and overcome ICAM-1 mediated immune effector suppression. Additionally, isogenic tumor cell lines with silenced ICAM-1 expression were more susceptible to antibody–drug conjugate (ADCs) cytotoxicity than parental cells. This effect appeared to correlate with membrane ICAM-1 binding to the IgG1 component that reduced ADC internalization, a function important for maximal target cell killing. These findings highlight a novel mechanism by which tumors can suppress the host's immune system for survival and offer new concepts for engineering antibody-based therapeutics that are refractory to ICAM-1 immunosuppression.

Abstract Image

ICAM-1在癌症中过度表达,并对包括抗体-药物偶联物在内的基于抗体的治疗产生负面影响。
体液免疫利用抗体和免疫效应细胞介导失调的癌细胞杀伤。这些机制被称为体液免疫肿瘤学(HIO)。HIO免疫抑制是由称为HIO因子的肿瘤产生的蛋白介导的。结合患者血清分析和文献检索,我们筛选了一些样本,以确定它们是否抑制了HIO。在此,我们发现ICAM-1(细胞间粘附分子1)可以结合igg1型抗体并抑制其免疫效应活性。通过一系列诱变,我们在IgG1CH3结构域中发现了ICAM-1结合所必需的独特基序,该基序抑制抗体依赖性细胞毒性和补体依赖性细胞毒性。CH3结构域内的保守氨基酸取代能够消除ICAM-1结合并克服ICAM-1介导的免疫效应抑制。此外,沉默ICAM-1表达的等基因肿瘤细胞系比亲本细胞更容易受到抗体-药物偶联(adc)细胞毒性的影响。这种效应似乎与膜ICAM-1与IgG1组分的结合有关,IgG1组分减少了ADC内化,这是最大限度杀死靶细胞的重要功能。这些发现强调了肿瘤抑制宿主免疫系统生存的新机制,并为基于ICAM-1免疫抑制的工程抗体治疗提供了新的概念。
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来源期刊
CiteScore
8.30
自引率
3.70%
发文量
224
审稿时长
2 months
期刊介绍: The European Journal of Immunology (EJI) is an official journal of EFIS. Established in 1971, EJI continues to serve the needs of the global immunology community covering basic, translational and clinical research, ranging from adaptive and innate immunity through to vaccines and immunotherapy, cancer, autoimmunity, allergy and more. Mechanistic insights and thought-provoking immunological findings are of interest, as are studies using the latest omics technologies. We offer fast track review for competitive situations, including recently scooped papers, format free submission, transparent and fair peer review and more as detailed in our policies.
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