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 对于没有特定靶向疗法的癌症，癌症免疫疗法是一种有前途的方法。 事实证明，各种形式的免疫疗法，包括检查点封锁免疫疗法 通过增强T细胞介导的免疫反应。这些疗法导致明显和持续的临床 反应，但仅在有限的患者和癌症类型中。抗肿瘤免疫反应需要 肿瘤抗原的功能呈现和有利于既有免疫效应子的微环境。到 在癌细胞上执行细胞毒性，CD8+细胞毒性T淋巴细胞（CTL）识别肿瘤抗原 呈现在癌细胞的主要组织相容性复合物I类（MHC-I）复合物上，并触发 癌细胞发生程序性细胞死亡。为了逃避免疫监测，癌细胞采用了各种 直接或间接涉及的MHC-I分子或其他蛋白质表达的机制 在抗原加工和表现中。下调似乎比完全消除更普遍 MHC-I表达的原因是，后者使癌细胞易受天然杀手（NK）细胞的作用。 肿瘤细胞上的抗原表现增加可能具有治疗意义，因为它使肿瘤细胞更多 容易受到CTL的影响。 在初步研究中，我们确定了一种膜蛋白Mal2，是一个重要的参与者，可降低 乳腺癌细胞上的抗原表现并抑制肿瘤浸润CD8+ T细胞的细胞毒性。到 促进临床前研究MAL2抑制作用，我们已经对小鼠产生了单克隆抗体 MAL2。我们将测试MAL2抑制剂（MAL2 MAB）在小鼠乳腺肿瘤模型中的抗肿瘤作用。我们将 还可以确定MAL2抑制剂在增强免疫检查点的疗效方面的治疗活性 封锁免疫疗法。