Augmenting the Immunogenicity of Melanoma Through Manipulation of Histone Deacet

通过组蛋白 Deacet 的操作增强黑色素瘤的免疫原性

• 批准号: 8556443
• 负责人: EDUARDO M. SOTOMAYOR
• 金额: $ 27.64万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8556443
• 关键词: Address; Animal Model; Antibodies; Antigen-Presenting Cells; Antigens; Apoptosis; Attention; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; CTLA4 gene; Cell Cycle Arrest; Cell Proliferation; Cell physiology; Cells; Clinical; Collaborations; Disease; Epigenetic Process; Face; Genetic; HDAC6 gene; Hand; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Human; Immune; Immune Tolerance; Immune response; Immunity; Immunobiology; Immunologics; Immunology; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; In Vitro; Innovative Therapy; Interferons; Interleukin-10; Knowledge; Laboratories; Lead; Malignant Neoplasms; Melanoma Cell; Metastatic Melanoma; Molecular; Mus; Outcome; Pathology; Pathway interactions; Patients; Phase I Clinical Trials; Production; Property; Resistance; Role; STAT3 gene; Safety; Sampling; Signal Transduction; Skin Cancer; Staging; T cell regulation; T cell response; T-Lymphocyte; Testing; Toxic effect; Treatment Efficacy; base; clinical effect; clinically significant; combinatorial; cytokine; frontier; immunogenic; immunogenicity; immunoregulation; improved; in vivo; inhibitor/antagonist; insight; melanoma; neoplastic cell; novel; novel therapeutic intervention; phase 1 study; response; tool; tumor; tumor immunology

In spite of the progress made in the understanding of the biology, genetics and immunology of melanoma, the outcome for patients with advanced-stage disease has remained poor. A step forward toward better therapies was recently provided by the improvement in overall survival observed in melanoma patients treated with an anti-CTLA4 antibody. Attempts to further augment the efficacy of this treatment would still face however a variety of immunosuppressive factors operative in melanoma-bearing hosts. Among those, one that has gained much attention is the ability of melanoma tumors to induce T-cell tolerance. Our studies to date of the epigenetic regulation of T-cell unresponsiveness point to histone deacetylase inhibitors (HDI) as promising immunomodulatory compounds given their dual ability to influence the immunogenicity of melanoma tumors and enhance T-cell function. These observations together with our additional findings that HDAC6 and HDAC11 regulates melanoma immunogenicity and T-cell responsiveness respectively, provided the rationale to mechanistically address the role of HDACs in melanoma immunobiology. The hypothesis to be tested is therefore whether epigenetic manipulation of specific HDACs might augment the immunogenicity of melanoma cells and/or augment T-cell responses leading to breaking of immune tolerance and enhancement of the efficacy of CTLA4 blockade. The animal models, molecular and pharmacological tools we have in hands together with the access (through the Pathology Core of this SPORE) to human melanoma samples would allow us to gain insights into the role of HDAC6 in melanoma proliferation, survival and immunogenicity (Aim 1), and the role of HDAC11 in T-cell anti-melanoma immunity (Aim 2). In addition, the expertise provided by the Clinical Core will allow the successful completion of a Phase I clinical trial aimed to assess the safety and immunologic effects of HDAC inhibition in combination with an anti-CTLA4 antibody in patients with stage IV melanoma (Aim 3). The new knowledge to be generated by this team effort would lead to novel epigenetic-based immunotherapy that by overcoming the remarkable barrier of melanoma-induced T-cell tolerance would improve the efficacy of CTLA4 blockade.

尽管在对黑色素瘤的生物学、遗传学和免疫学的理解方面取得了进展，但晚期疾病患者的预后仍然很差。最近，在接受抗CTLA4抗体治疗的黑色素瘤患者中观察到总存活率的改善，这为更好的治疗向前迈进了一步。然而，进一步提高这种治疗效果的尝试仍将面临多种免疫抑制因素对黑色素瘤宿主的作用。其中一个备受关注的是黑色素瘤诱导T细胞耐受的能力。到目前为止，我们对T细胞无反应性的表观遗传调控的研究表明，组蛋白脱乙酰酶抑制剂(HDI)具有影响黑色素瘤肿瘤免疫原性和增强T细胞功能的双重能力，因此是很有前途的免疫调节化合物。这些观察，再加上我们关于HDAC6和HDAC11分别调节黑色素瘤免疫原性和T细胞反应性的更多发现，为从机制上解决HDACs在黑色素瘤免疫生物学中的作用提供了理论基础。因此，需要检验的假设是，对特定HDAC的表观遗传操作是否可能增强黑色素瘤细胞的免疫原性和/或增强T细胞反应，从而打破免疫耐受并增强CTLA4阻断的效果。我们手中的动物模型、分子和药理学工具，以及(通过这个孢子的病理核心)获取人类黑色素瘤样本的途径，将使我们能够深入了解HDAC6在黑色素瘤增殖、存活和免疫原性中的作用(目标1)，以及HDAC11在T细胞抗黑色素瘤免疫中的作用(目标2)。此外，临床核心中心提供的专业知识将使一项旨在评估HDAC抑制与抗CTLA4抗体联合治疗IV期黑色素瘤患者的安全性和免疫学效果的第一阶段临床试验成功完成(AIM 3)。这一团队的努力将产生新的知识，这将导致基于表观遗传的新型免疫疗法，通过克服黑色素瘤诱导的T细胞耐受的显着障碍，将提高CTLA4阻断的疗效。