Intervention of immune tolerance by small molecules to enhance immune therapy

小分子干预免疫耐受，增强免疫治疗

• 批准号: 8267089
• 负责人: Shu-Hsia Chen
• 金额: $ 33.95万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267089
• 关键词: Ablation; B-Lymphocytes; Blood specimen; Bone Marrow; Bone Marrow Neoplasms; CSF1R gene; Cancer Patient; Carcinoma; Cell Count; Cells; Clinical; Clinical Protocols; Colon; Colonic Neoplasms; Colorectal Cancer; Complement; Dendritic Cells; Development; Disseminated Malignant Neoplasm; Electron Microscopy; Foundations; Gleevec; Goals; Growth; Health; Hepatic; Imatinib mesylate; Immune; Immune Tolerance; Immune response; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Intervention; Large Intestine Carcinoma; Lead; Leukocytes; Ligands; Macrophage-1 Antigen; Malignant Neoplasms; Mediating; Metastatic Carcinoma; Modality; Modeling; Molecular Profiling; Molecular Target; Mus; Mutant Strains Mice; Myelogenous; Neoplasm Metastasis; Nitric Oxide; Pathway interactions; Patients; Phenotype; Population; Prevention; Production; Proto-Oncogene Protein c-kit; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulatory T-Lymphocyte; Signal Pathway; Signal Transduction; Spleen; Stem Cell Factor; Suppressor-Effector T-Lymphocytes; Sutent; T cell anergy; T cell response; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Treatment Efficacy; Tumor Burden; Tumor Immunity; Tumor Suppression; Tyrosine Kinase Inhibitor; Wright-Giemsa Staining Method; base; cancer therapy; cell type; cellular targeting; clinically relevant; congenic; cytokine; improved; in vivo; inhibitor/antagonist; mast cell; metastatic colorectal; monocyte; neoplastic cell; novel; novel therapeutics; peripheral blood; pre-clinical; prevent; receptor; response; reverse tolerance; small molecule; sunitinib malate; tumor

DESCRIPTION (provided by applicant): A growing body of evidence suggests that host immune cells with a suppressive phenotype pose a significant hurdle to successful immune enhancing therapy for cancer. Among the suppressor cells, T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) have been shown to increase significantly in hosts with advanced malignancies. Previously, we found that the growth of various carcinomas induced a significant increase in the numbers of MDSC in tumor, spleen, and bone marrow of tumor-bearing mice. More interestingly, we have demonstrated that MDSC can mediate the suppression of the tumor-specific T-cell response through the induction of T-cell anergy and the development of Treg in vitro and in tumor-bearing mice. These results provide strong evidence of an in vivo immunoregulatory function of MDSC in the establishment of tumor-specific tolerance and the development of Treg in tumor-bearing hosts. To achieve persistent anti- tumor immunity and to improve the therapeutic effect of immunomodulatory treatments, the tumor-induced immunosuppression must be overcome and investigated. Our preliminary results indicate that ckit ligand (stem cell factor) expressed by tumor cells may be required for MDSC accumulation in tumor bearing mice and that blocking the ckit ligand/ckit receptor interaction can prevent the development of Treg and reverse tolerance induced by MDSC. We hypothesize that: 1) Targeted pharmacological disruption of c-kit receptor signaling by using small molecule inhibitors can prevent the accumulation of MDSCs and Treg suppression, thereby increasing the therapeutic efficacy of immune-based therapy; 2) Disruption of ckit receptor tyrosine kinase activation pathway can stimulate Th1 responses and prevent T-cell tolerance and Th2 polarization in mice with advanced malignancies; 3) Leukocyte subsets required for the establishment of immune tolerance in tumor microenvironment can be modulated by blocking the signaling pathways of ckit. Three specific aims will be pursued: 1) To study the effect of receptor tyrosine kinase inhibitors on MDSC accumulation, MDSC-mediated Treg development, and suppressive function Treg in mice with large tumor burdens; 2) To study the underlying mechanisms and cell types that are involved in the immune tolerance, which can be disrupted by class III receptor tyrosine kinase inhibitors in advanced murine colon tumor models; 3) To study the effect of small molecule inhibitors on the expansion of MDSC, Treg, and immune tolerance in treated cancer patients. Successful completion of these studies will result in a better understanding of the mechanisms of action by these small compounds and immune tolerance, which may lead to the discovery of novel targets for the intervention in tumor-associated immunosuppression. The information will be utilized as the scientific foundation for the development of a novel therapeutic modality that can counteract the immune suppression associated with advanced malignancy. The ablation of immune tolerance should significantly augment the efficacy of existing immune-based therapies for treatment of advanced metastatic colorectal carcinomas. PUBLIC HEALTH RELEVANCE: The goal of this project is 1) To investigate whether pharmacological inhibition of signaling of tumor factors can prevent MDSC accumulation and can intervene with the suppressive activities of MDSC; (2) To identify the underlying mechanisms and cytokines and cell subsets that are involved in small molecule-mediated blockade of Treg expansion and reversion of T-cell tolerance. The therapeutic potential of modulating the suppressive functions through the use of receptor tyrosine kinase inhibitors to complement existing immune based strategies for treating advanced large tumors will be evaluated; (3) To study the effect of tyrosine kinase inhibitors (Gleevec and Sutent) on MDSC suppressive activities and anti-tumor responses in cancer patients.

描述（由申请人提供）：越来越多的证据表明，具有抑制性表型的宿主免疫细胞对癌症的成功免疫增强治疗构成了重大障碍。在抑制细胞中，调节性T细胞（TCFs）和髓源性抑制细胞（MDSC）已被证明在晚期恶性肿瘤宿主中显著增加。以前，我们发现，各种肿瘤的生长诱导MDSC在肿瘤，脾脏和骨髓中的荷瘤小鼠的数量显着增加。更有趣的是，我们已经证明，MDSC可以通过诱导T细胞无能和Treg在体外和荷瘤小鼠中的发展来介导肿瘤特异性T细胞应答的抑制。这些结果为MDSC在肿瘤特异性耐受的建立和Treg在荷瘤宿主中的发展中的体内免疫调节功能提供了强有力的证据。为了实现持久的抗肿瘤免疫和提高免疫调节治疗的治疗效果，必须克服和研究肿瘤诱导的免疫抑制。我们的初步结果表明，ckit配体（干细胞因子）表达的肿瘤细胞可能需要MDSC的积累在荷瘤小鼠和阻断ckit配体/ckit受体的相互作用，可以防止Treg的发展和逆转MDSC诱导的耐受。我们假设：1）通过使用小分子抑制剂靶向药理学破坏c-kit受体信号传导可以防止MDSC的积累和Treg抑制，从而增加基于免疫的治疗的治疗功效; 2）破坏ckit受体酪氨酸激酶活化途径可以刺激晚期恶性肿瘤小鼠中的Th 1应答并防止T细胞耐受和Th 2极化; 3）阻断ckit信号通路可调节肿瘤微环境中免疫耐受建立所需的白细胞亚群。本研究的目的有三：1）研究受体酪氨酸激酶抑制剂对MDSC蓄积、MDSC介导的Treg发育和肿瘤负荷小鼠Treg抑制功能的影响; 2）研究晚期小鼠结肠肿瘤模型中III类受体酪氨酸激酶抑制剂可破坏免疫耐受的潜在机制和细胞类型; 3）研究小分子抑制剂对治疗的癌症患者中MDSC、Treg和免疫耐受的扩增的影响。这些研究的成功完成将导致更好地理解这些小化合物的作用机制和免疫耐受性，这可能导致发现新的靶点用于干预肿瘤相关的免疫抑制。这些信息将被用作开发一种新的治疗方式的科学基础，这种治疗方式可以抵消与晚期恶性肿瘤相关的免疫抑制。免疫耐受的消除将显著增强现有基于免疫的治疗晚期转移性结直肠癌的疗效。 公共卫生关系：本项目的目的是：1）研究药物抑制肿瘤因子信号传导是否可以防止MDSC积聚并干预MDSC的抑制活性;（2）确定小分子介导的Treg扩增阻断和T细胞耐受逆转的潜在机制和细胞因子和细胞亚群。通过使用受体酪氨酸激酶抑制剂来调节抑制功能以补充现有的基于免疫的治疗晚期大肿瘤的策略的治疗潜力将被评估;（3）研究酪氨酸激酶抑制剂（Gleevec和Sutent）对癌症患者MDSC抑制活性和抗肿瘤应答的影响。