Role of Immune Regulatory Pathways in BRAF Targeted Therapy In Melanoma

项目2将调查免疫反应在决定BRAF进程中的作用 突变型黑色素瘤以及如何利用这些知识开发有效的联合治疗方法 基于免疫调节分子与靶向致癌BRAF药物的协同作用的方案(S)。 与BRAF靶向反应性和耐药性相关的免疫调节分子的表达 人类和小鼠黑色素瘤的治疗将通过分子、免疫组织学和 流式细胞术的方法。由于最近抗CTLA-4治疗黑色素瘤的前景看好。 项目2还将分析Ahti-CTLA-4治疗如何改变样本中的肿瘤微环境 使用这种免疫检查点调节剂治疗黑色素瘤的患者。功能和临床验证 对BRAF突变型黑色素瘤免疫调节靶点的研究最初将确定BRAF靶向 治疗对人PBMCs、TIL和IBIP小鼠抗肿瘤免疫的影响 对BRAF治疗的反应性和抵抗力的设置。进一步的研究将探索 单独阻断免疫调节靶点及与BRAF靶向联合治疗策略 治疗肿瘤消退与抗肿瘤免疫。初步的功能研究将集中在 CTLA-4和PD-1/PDL通路，因为它们在黑色素瘤中具有强大的免疫调节作用。这 BRAF突变型人和小鼠黑色素瘤免疫反应的详细特征 肿瘤的生长、治疗和耐药性将提供对肿瘤免疫成分的分子洞察 BRAF靶向治疗和引导BRAF靶向治疗和BRAF靶向治疗的合理组合的开发 免疫疗法，以最大限度地减少耐药性，实现持久缓解。

Project 2 will investigate the role of immune responses in dictating the course of BRAF mutant melanoma and how such knowledge can be exploited to develop effective combination therapeutic regimen(s) based on synergy between immunomodulatory molecules and drugs targeting oncogenic BRAF. Expression of immunoregulatory molecules associated with responsiveness and resistance to BRAFtargeted therapy in human and murine melanoma will be determined using molecular, immunohistologic and flow cytometry approaches. Because of the recent therapeutic promise of anti-CTLA-4 therapy in melanoma. Project 2 also will analyze how ahti-CTLA-4 therapy alters the tumor microenvironment in samples from patients with melanoma treated with this immune checkpoint modulator. Functional and clinical validation studies of immunomodulatory targets in BRAF-mutant melanoma initially will determine how BRAF-targeted therapy impacts anti-tumor immunity using human PBMCs and TILs from treated patients and IBIP mice in the settings of responsiveness and resistance to BRAF therapy. Further studies will explore the impact of blocking immunomodulatory targets individually and in combination therapeutic strategies with BRAFtargeted therapy on tumor regression and anti-tumor immunity. Initial functional studies will focus on the CTLA-4 and PD-1/PDL pathways because of their potent immunomodulatory effects in melanoma. This detailed characterization of the immune response in BRAF mutant human and mouse melanomas during tumor growth, treatment and resistance will provide molecular insights into the immune components of BRAF-targeted therapy and guide development of rational combinations of BRAF-targeted therapy and immunotherapy to minimize resistance and achieve durable remission.