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

基本信息

批准号：
8074566
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
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8074566
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

项目摘要

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，具有抑制表型的宿主免疫细胞对成功的癌症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 (Treg) 和骨髓源性抑制细胞 (MDSC) 在患有晚期恶性肿瘤的宿主中显着增加。此前，我们发现各种癌症的生长会导致荷瘤小鼠的肿瘤、脾脏和骨髓中MDSC数量显着增加。更有趣的是，我们已经证明，MDSC 可以在体外和荷瘤小鼠中通过诱导 T 细胞无反应性和 Treg 发育来介导肿瘤特异性 T 细胞反应的抑制。这些结果提供了强有力的证据，证明MDSC在肿瘤特异性耐受的建立和荷瘤宿主中Treg的发育中具有体内免疫调节功能。为了实现持久的抗肿瘤免疫并提高免疫调节治疗的疗效，必须克服和研究肿瘤引起的免疫抑制。我们的初步结果表明，肿瘤细胞表达的ckit配体（干细胞因子）可能是荷瘤小鼠中MDSC积累所必需的，阻断ckit配体/ckit受体相互作用可以阻止Treg的发展和MDSC诱导的逆转耐受。我们假设：1）使用小分子抑制剂对c-kit受体信号传导进行靶向药理学破坏可以防止MDSC的积累和Treg抑制，从而提高免疫疗法的疗效； 2) 破坏ckit受体酪氨酸激酶激活通路可刺激晚期恶性肿瘤小鼠的Th1反应并阻止T细胞耐受和Th2极化； 3）通过阻断ckit信号通路，可以调节肿瘤微环境中建立免疫耐受所需的白细胞亚群。我们将追求三个具体目标：1）研究受体酪氨酸激酶抑制剂对大肿瘤负荷小鼠中MDSC积累、MDSC介导的Treg发育以及抑制Treg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癌症治疗患者MDSC、Treg和免疫耐受扩增的影响。这些研究的成功完成将有助于更好地了解这些小化合物的作用机制和免疫耐受性，从而可能发现干预肿瘤相关免疫抑制的新靶点。这些信息将被用作开发一种新型治疗方式的科学基础，这种方式可以抵消与晚期恶性肿瘤相关的免疫抑制。免疫耐受的消除应该会显着增强现有基于免疫疗法治疗晚期转移性结直肠癌的疗效。公共健康相关性：该项目的目标是 1) 研究肿瘤因子信号传导的药物抑制是否可以阻止 MDSC 积累并干预 MDSC 的抑制活性； (2) 确定参与小分子介导的 Treg 扩增阻断和 T 细胞耐受逆转的潜在机制以及细胞因子和细胞亚群。将评估通过使用受体酪氨酸激酶抑制剂调节抑制功能的治疗潜力，以补充现有的基于免疫的治疗晚期大肿瘤的策略； (3)研究酪氨酸激酶抑制剂(格列卫和索坦)对癌症患者MDSC抑制活性和抗肿瘤反应的影响。