CD73 and tumor immunity

CD73与肿瘤免疫

基本信息

批准号：
8223149
负责人：
Bin Zhang
金额：
$ 14.24万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8223149
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 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

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. PUBLIC HEALTH RELEVANCE: By the completion of these studies, we will gain insight into the immunosuppressive mechanisms of CD73 in the cancer microenvironment and, more importantly, we will validate a novel and feasible strategy of cancer treatment. This therapeutic approach may enhance chemotherapy and particularly T cell-based therapy by enhancing the adaptive immune response machinery, which may increase the function of tumor-infiltrating CD8+ T lymphocytes, and subsequently lead to improved survival in cancer patients.

描述（由申请人提供）：癌症免疫疗法的前景尚未转化为临床成功，因为癌症患者体内作用的免疫抑制机制可以阻断有效的抗肿瘤免疫，因此，为了通过免疫疗法根除癌症，必须采用肿瘤诱导的免疫抑制。我们最近证明了一种新的肿瘤内在免疫抑制机制，其中肿瘤源性 CD73 作为胞外酶发挥作用，产生限制细胞外的腺苷。我们还发现，恶性肿瘤中 CD73 的表达与肿瘤浸润效应 T 细胞的不良免疫状态密切相关，我们使用 CD73 siRNA 处理的初步数据令人兴奋。肿瘤细胞和 CD73-/- 小鼠表明，肿瘤和宿主 CD73 的消融以 T 细胞依赖性方式协同抑制肿瘤生长，观察到类似的抗肿瘤作用。使用选择性抑制剂 a,¿ 药物阻断 CD73 -亚甲基腺苷 5'-二磷酸 (APCP) 因此，我们研究肿瘤和宿主 CD73 通过其酶活性来防止传入的抗肿瘤 T 细胞破坏肿瘤。肿瘤细胞或宿主细胞上的表达会影响抗肿瘤 T 细胞反应，因为内源性抗肿瘤免疫即使恢复，通常也是不充分且短暂的，因此除非与其他形式的联合治疗，否则靶向 CD73 癌症治疗可能不是最佳的。免疫疗法，例如过继性 T 细胞转移或 DC 疫苗将被测试，以评估内源性和过继性转移的抗肿瘤 CD8+ T 细胞免疫与 CD73 消除相结合的疗效。治疗方面，我们将探索使用 APCP 或抗 CD73 单克隆抗体 (mAb) 联合 T 细胞疗法抑制 CD73 的临床前潜力。公共健康相关性：通过完成这些研究，我们将深入了解 CD73 在癌症微环境中的免疫抑制机制，更重要的是，我们将验证一种新颖且可行的癌症治疗策略，这种治疗方法可能会增强化疗，尤其是化疗。基于 T 细胞的治疗通过增强适应性免疫反应机制，可能会增加肿瘤浸润 CD8+ T 淋巴细胞的功能，从而提高癌症患者的生存率。