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CD73 and Tumor Immunity-CD73 and CTLA-4 combination Blockade in Ovarian Cancer

CD73 和肿瘤免疫——CD73 和 CTLA-4 联合阻断卵巢癌

基本信息

批准号：
8628468
负责人：
Bin Zhang
金额：
$ 5.53万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8628468
关键词：
Ablation Adenosine Adoptive Transfer Antigens Biological Assay Blood Circulation Bone Marrow CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Cells Clinical Data Diphosphates Endothelial Cells Enzymes Flow Cytometry Generations Human Immune Immune response Immunity Immunohistochemistry Immunosuppression Immunosuppressive Agents Immunotherapy In Vitro Kinetics Lead Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Mediating Memory Modeling Monoclonal Antibodies Mus Peritoneal Population Production Purinergic P1 Receptors Receptor Signaling Regulatory T-Lymphocyte Role Signal Transduction Small Interfering RNA T cell response T cell therapy T-Lymphocyte Testing Therapeutic Translating Tumor Immunity Tumor Tissue Tumor-Derived Vaccines cancer immunotherapy cancer therapy carbene cell motility chemotherapy cytokine efficacy testing extracellular immunogenic improved in vivo inhibitor/antagonist insight lymph nodes migration neoplastic cell novel ovarian neoplasm perforin pre-clinical prevent public health relevance reconstitution subcutaneous success tumor tumor growth tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): The promises of cancer immunotherapy have not been translated into clinical successes because immune-suppressive mechanisms that act in cancer patients can block effective anti-tumor immunity. Therefore, to eradicate cancers by immunotherapy, tumor-induced immunosuppression must be overcome. We have recently demonstrated a novel tumor-intrinsic immunosuppressive mechanism whereby tumor-derived CD73 functions as an ecto-enzyme to produce extracellular adenosine which limits anti-tumor T cell immunity to promote tumor growth via adenosine receptor (AR) signaling. We also found that CD73 expression in malignant cancers was closely associated with poor immune status of tumor infiltrating effector T cells. Our exciting preliminary data using CD73 siRNA-treated tumor cells and CD73-/- mice indicated that ablation of both tumor and host CD73 synergistically inhibited tumor growth in a T cell-dependent manner. A similar anti-tumor effect was observed by pharmacological blockade of CD73 using the selective inhibitor a,¿-methylene adenosine 5'-diphosphate (APCP). Thus, we hypothesize that both tumor and host CD73 through their enzymatic activity prevent tumor destruction by incoming anti-tumor T cells. We here plan to further clarify the mechanisms of tumor protection by which CD73 expression on either tumor cells or host cells impacts anti-tumor T cell responses. Because endogenous anti-tumor immunity, even if restored, is often insufficient and transient, targeted CD73 cancer therapy may not be optimal unless combined with other forms of immunotherapy, such as adoptive T cell transfer or DC vaccines. Several immunogenic tumors will be tested to assess the efficacy of endogenous and adoptively transferred anti-tumor CD8+ T cell immunity in combination with CD73 ablation. Finally, to establish the translational relevance of targeted CD73 therapy, we will explore the preclinical potential of inhibiting CD73 using APCP or an anti-CD73 monoclonal antibody (mAb) combined with T cell therapy.

描述(申请人提供)：癌症免疫治疗的承诺尚未转化为临床成功，因为作用于癌症患者的免疫抑制机制可能会阻碍有效的抗肿瘤免疫。因此，要通过免疫治疗来根除癌症，必须克服肿瘤诱导的免疫抑制。我们最近证实了一种新的肿瘤内源性免疫抑制机制，通过肿瘤来源的CD73作为胞外酶产生胞外腺苷，从而限制抗肿瘤T细胞免疫，通过腺苷受体(AR)信号转导促进肿瘤生长。我们还发现CD73在恶性肿瘤中的表达与肿瘤浸润性效应T细胞免疫状态低下密切相关。我们使用CD73 siRNA处理的肿瘤细胞和CD73-/-小鼠的令人兴奋的初步数据表明，肿瘤和宿主CD73的消融以T细胞依赖的方式协同抑制肿瘤的生长。用选择性抑制剂α-亚甲基腺苷-5‘-二磷酸(APCP)阻断CD73也有类似的抗肿瘤作用。因此，我们假设肿瘤和宿主CD73都通过它们的酶活性来防止进入的抗肿瘤T细胞对肿瘤的破坏。我们计划进一步阐明CD73在肿瘤细胞或宿主细胞上的表达影响抗肿瘤T细胞应答的肿瘤保护机制。由于内源性抗肿瘤免疫，即使恢复，往往是不足的和短暂的，靶向CD73癌症治疗可能不是最佳的，除非与其他形式的免疫治疗相结合，如过继T细胞转移或DC疫苗。将对几种免疫原性肿瘤进行测试，以评估内源性和过继转移的抗肿瘤CD8+T细胞免疫结合CD73消融的疗效。最后，为了确定靶向CD73治疗的翻译相关性，我们将探索使用APCP或抗CD73单抗(MAb)联合T细胞治疗抑制CD73的临床前潜力。