Targeting MAL2-mediated endocytosis to enhance tumor cell antigen presentation

靶向 MAL2 介导的内吞作用以增强肿瘤细胞抗原呈递

• 批准号: 10734324
• 负责人: Xinna Zhang
• 金额: $ 46.69万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-14 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734324
• 关键词: Antibodies; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Apoptosis; Architecture; Autologous; Binding; Bioinformatics; Breast Cancer Cell; Breast Cancer Model; Breast Cancer therapy; CD8-Positive T-Lymphocytes; Cancer Biology; Cell membrane; Cells; Clathrin; Clinic; Clinical; Coculture Techniques; Complex; Cytotoxic T-Lymphocytes; Databases; Development; Docking; Down-Regulation; Endocytosis; Endocytosis Inhibition; Endocytosis Pathway; Endosomes; Extracellular Domain; Genes; Human; Immune; Immune Evasion; Immune response; Immune system; Immunocompetent; Immunologic Surveillance; Immunology; Immunotherapy; Infiltration; Lead; Major Histocompatibility Complex; Malignant Neoplasms; Mammary Neoplasms; Mediating; Membrane Proteins; Monoclonal Antibodies; Mus; Mutation; Natural Killer Cells; Organoids; PIK3CG gene; Pathway interactions; Patients; Play; Pre-Clinical Model; Predisposition; Process; Proteins; Protocols documentation; Reaction; Research Personnel; Role; Standardization; T-Lymphocyte; Testing; Therapeutic; Tumor Antigens; Tumor Tissue; anti-PD-1; anti-tumor immune response; antigen binding; antitumor effect; cancer cell; cancer genomics; cancer immunotherapy; cancer type; cell mediated immune response; cytotoxic CD8 T cells; cytotoxicity; immune cell infiltrate; immune checkpoint blockade; improved; in silico; inhibitor; malignant breast neoplasm; neoplastic cell; preclinical study; preservation; response; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor initiation; tumor microenvironment

Project Abstract Cancer immunotherapy is a promising approach for cancers with no or limited specific targeted therapies. Various forms of immunotherapy, including checkpoint blockade immunotherapies, are proving to be effective by boosting T cell-mediated immune responses. These therapies lead to marked and sustained clinical responses, but only in a limited number of patients and cancer types. Anti-tumor immune responses require functional presentation of tumor antigens and a microenvironment that favors competent immune effectors. To execute the cytotoxicity on cancer cells, the CD8+ cytotoxic T lymphocytes (CTLs) recognize tumor antigens presented on the major histocompatibility complex class I (MHC-I) complex of the cancer cell and trigger the cancer cell to undergo programmed cell death. To evade immune surveillance, cancer cells employ various mechanisms to downregulate the expression of MHC-I molecules or other proteins directly or indirectly involved in antigen processing and presentation. Downregulation appears to be more common than complete elimination of MHC-I expression because the latter renders cancer cells susceptible to the action of natural killer (NK) cells. Increased antigen presentation on tumor cells can be of therapeutic significance since it makes tumor cells more susceptible to the CTLs. In the preliminary study, we identified a membrane protein, MAL2, as an important player that reduces the antigen presentation on breast cancer cells and suppresses the cytotoxicity of tumor-infiltrating CD8+ T cells. To facilitate the preclinical studies for MAL2 inhibition, we have generated monoclonal antibodies against the mouse MAL2. We will test the antitumor effect of MAL2 inhibitor (MAL2 mAb) in mouse breast tumor models. We will also determine the therapeutic activity of MAL2 inhibitor in enhancing the efficacy of immune checkpoint blockade immunotherapy.

项目摘要 癌症免疫治疗是一种很有前途的方法，用于没有或有限的特异性靶向治疗的癌症。 包括检查点阻断免疫疗法在内的各种形式的免疫疗法被证明是有效的 通过增强T细胞介导的免疫反应。这些疗法导致显著和持续的临床 反应，但仅限于有限数量的患者和癌症类型。抗肿瘤免疫反应需要 肿瘤抗原的功能呈递和有利于有能力的免疫效应物的微环境。到 CD 8+细胞毒性T淋巴细胞（CTL）识别肿瘤抗原， 在癌细胞的主要组织相容性复合物I类（MHC-I）复合物上呈递，并触发癌细胞的免疫反应。 癌细胞经历程序性细胞死亡。为了逃避免疫监视，癌细胞利用各种 下调MHC-I分子或其他直接或间接参与的蛋白质表达的机制 在抗原加工和呈递中的作用。下调似乎比完全消除更常见 MHC-I的表达，因为后者使癌细胞对自然杀伤（NK）细胞的作用敏感。 肿瘤细胞上增加的抗原呈递可以具有治疗意义，因为它使肿瘤细胞更多地 对CTL敏感 在初步研究中，我们鉴定了一种膜蛋白MAL 2，它是降低细胞凋亡的重要因素。 在乳腺癌细胞上的抗原呈递和抑制肿瘤浸润性CD 8 + T细胞的细胞毒性。到 为了促进MAL 2抑制的临床前研究，我们已经产生了针对小鼠的单克隆抗体， MAL2.我们将在小鼠乳腺肿瘤模型中测试MAL 2抑制剂（MAL 2 mAb）的抗肿瘤作用。我们将 还确定了MAL 2抑制剂在增强免疫检查点功效方面的治疗活性， 阻断免疫疗法