Therapeutic Targeting of Immune Evasion from the MICA - NKG2D Pathway

MICA 免疫逃避的治疗靶向 - NKG2D 通路

• 批准号: 10359199
• 负责人: Kai W Wucherpfennig
• 金额: $ 51.04万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359199
• 关键词: Advanced Malignant Neoplasm; Antibodies; Antibody-mediated protection; CD8-Positive T-Lymphocytes; CD94 Antigen; CTLA4 gene; Cancer Patient; Cancer cell line; Cell surface; Cells; Cellular Stress; Clinical Trials; Combined Modality Therapy; Complement; Data; Disease; Disease Progression; Effector Cell; FCGR3B gene; Family; Fc Receptor; Flow Cytometry; Future; Gene Expression; Genes; Genomics; Goals; Growth Factor Receptors; Heat shock proteins; Heterozygote; Histocompatibility Antigens Class I; Human; Immune; Immune Evasion; Immune Targeting; Immunity; Immunocompetent; Immunotherapy; Impairment; Ligands; Lymphocyte; MHC Class I Genes; MICA protein; MMP14 gene; Malignant Neoplasms; Matrix Metalloproteinases; Mediating; Melanoma Cell; Membrane; Modeling; Molecular; Monoclonal Antibodies; Mus; NK Cell Activation; Natural Killer Cells; Neoplasm Metastasis; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Population; Process; Protein Analysis; Protein Disulfide Isomerase; Proteins; Receptor Signaling; Resected; Resistance; Serum; Site; Stimulator of Interferon Genes; Stress; Substrate Specificity; Surface; T-Lymphocyte; Therapeutic; Tumor Immunity; cancer immunotherapy; cell transformation; cytotoxic; cytotoxicity; density; design; experimental study; genetic approach; humanized mouse; immune checkpoint blockade; in vivo; inhibiting antibody; ipilimumab; loss of function mutation; melanoma; mouse model; neoantigens; neoplastic cell; novel strategies; programmed cell death protein 1; protein expression; receptor; receptor binding; refractory cancer; resistance mechanism; single cell analysis; single-cell RNA sequencing; small molecule inhibitor; therapeutic target; tumor

Project Summary MICA and MICB (MICA/B) are stress proteins that are frequently expressed by diverse types of human cancer as a consequence of genomic damage, but are rarely expressed by healthy cells. MICA/B serve as ligands for the NKG2D receptor expressed by all cytotoxic lymphocytes, including CD8 T cells,  T cells, NKT cells and NK cells, enabling recognition and elimination of stressed and transformed cells. Proteolytic shedding of MICA/B is a major immune evasion mechanism from NKG2D-mediated tumor immunity in many human cancers. This shedding process involves unfolding of the MICA/B 3 domain by the action of the disulfide isomerase ERp5 which enables MICA/B cleavage by proteases belonging to the ADAM and MMP families. It is not feasible to inhibit shedding in vivo with small molecule inhibitors because the relevant proteases have broad substrate specificities. We developed an approach to inhibit MICA/B shedding by designing antibodies that sterically block the shedding site in the MICA/B 3 domain. These antibodies potently inhibit MICA/B shedding by a diverse panel of human cancer cell lines and thereby substantially increase the cell surface density of these stimulatory NKG2D ligands. As a consequence, MICA/B antibodies induce strong killing of human tumor cells by NK cells. These antibodies also induce immunity in mouse models of metastasis. Single-cell RNA-seq data show that a MICA/B antibody induces a striking shift among metastasis-infiltrating NK cells to an activated and cytotoxic state. We have also validated these antibodies in a humanized mouse model in which human NK cells target metastases formed by human tumor cells. Many human cancers are resistant to immunotherapy with checkpoint blockade through loss of MHC class I expression. However, MHC class I protein expression is not required for anti-tumor immunity mediated by innate T cell populations (NKT cells, T cells) and NK cells that all express the NKG2D receptor. The major goal of this project is to develop MICA/B antibodies as a therapeutic strategy for MHC class I deficient tumor cells that are resistant to conventional CD8 T cells. We have developed an integrated approach to study this important question in fully immunocompetent mouse models (Aim 1) as well as humanized mouse models and human tumor metastases (Aim 2). In Aim 1, we will examine the contribution of innate T cell and NK cell populations to MICA/B antibody mediated immunity against spontaneous metastases. In Aim 2, we will perform an in depth single-cell RNA-seq analysis of NKG2D-expressing innate T cell and NK cell population in human melanoma metastases. We will also use a humanized mouse model to develop combination therapies with established cancer therapeutics that enhance MICA/B expression and may therefore act synergistically with MICA/B antibodies. These studies will significantly advance the cancer immunotherapy field by developing novel approaches to target human cancers resistant to current immunotherapies.

项目摘要 云母和MICB（云母/B）是应力蛋白，经常由潜水员类型的人类癌症表达 由于基因组损伤，但很少由健康细胞表达。云母/B充当配体 由所有细胞毒性淋巴细胞表达的NKG2D受体，包括CD8 T细胞，T细胞，NKT细胞和NK 细胞，能够识别并消除压力和转化的细胞。云/B的蛋白水解脱落为 在许多人类癌症中，NKG2D介导的肿瘤免疫史的主要免疫进化机制。这 脱落过程涉及通过二硫键异构酶ERP5的作用来展开云母/b3域 这可以通过属于亚当和MMP家族的蛋白酶进行云母裂解。这是不可行的 用小分子抑制剂在体内抑制脱落，因为相关蛋白酶具有较宽的底物 特殊性。我们开发了一种方法来通过设计阻塞的抗体来抑制云母/B脱落 云母/B3域中的脱落位点。这些抗体可能会抑制各种各样的云母/B脱落 人类癌细胞系的面板，从而大大增加了这些刺激的细胞表面密度 NKG2D配体。因此，云母抗体会诱导NK细胞对人肿瘤细胞的强烈杀死。 这些抗体还诱导了小鼠转移模型中的免疫学。单细胞RNA-seq数据显示 云母/B抗体诱导转移浸入NK细胞之间的罢工转移到激活和细胞毒性 状态。我们还验证了人类小鼠模型中的这些抗体，其中人类NK细胞靶向 人类肿瘤细胞形成的转移。 许多人类癌症因失去MHC I类而抗免疫疗法，并具有检查点封锁 表达。但是，MHC I类蛋白表达不需要先天性介导的抗肿瘤免疫学 T细胞群（NKT细胞，t细胞）和NK细胞都表达NKG2D接收器。主要目标 该项目将开发云母抗体作为MHC I类特异性肿瘤细胞的治疗策略 对常规CD8 T细胞具有抗性。我们已经开发了一种综合方法来研究这一重要的 完全免疫能力的小鼠模型（AIM 1）以及人源化的小鼠模型和人类的问题 肿瘤转移（AIM 2）。在AIM 1中，我们将研究先天T细胞和NK细胞种群对 云母/B抗体介导的免疫支持对赞助转移。在AIM 2中，我们将进行深入 人黑色素瘤中表达NKG2D先天T细胞和NK细胞群的单细胞RNA-seq分析 转移。我们还将使用人源化的鼠标模型来开发与已建立的组合疗法 增强云/B表达的癌症疗法，因此可以与云母协同作用 抗体。这些研究将通过发展新颖 靶向抗当前免疫疗法的人类癌症的方法。