Translational Immunology

尽管在如何克服肿瘤相关的免疫抑制方面取得了进展，但许多因素，如T细胞淋巴细胞减少、T细胞功能障碍、循环抑制性调节性T淋巴细胞数量过高、肿瘤细胞PD-L1表达、肿瘤相关巨噬细胞（TAM）定向的抑制性以及免疫效应物在血脑屏障上的转运受损，都对胶质母细胞瘤的有效免疫治疗提出了挑战。我们的基础和转化研究主要集中在脑肿瘤、局部组织微环境和全身免疫反应之间的免疫相互作用。我们的目标是通过1)改善淋巴细胞功能和2)使肿瘤更容易受到免疫攻击来增强免疫治疗。我们正在研究肿瘤微环境的组成部分，如免疫调节细胞、缺氧和代谢因素对免疫功能的影响。我们也在研究由皮质类固醇和抗癌疗法引起的免疫衰竭的机制。最后，我们正在研究肿瘤细胞逃避免疫攻击的表观遗传和分子机制。免疫学项目有两个主要组成部分：基于免疫的脑肿瘤临床试验的免疫监测和阐明脑肿瘤患者免疫抑制的机制，重点关注医源性原因，如皮质类固醇的使用，缺乏新抗原和肿瘤微环境的影响。免疫监测将作为精子脑肿瘤临床试验的相关生物学，而脑肿瘤中免疫抑制的调节将作为未来基于假设的临床试验的基础。在与NOB PTRF和临床中心的合作中，我们正在进一步研究体内的实验性免疫疗法。最近有两项临床试验开放（17C0102免疫检查点抑制剂Nivolumab用于选择罕见中枢神经系统癌症患者；17C0034放射治疗联合替莫唑胺和派姆单抗伴或不伴SPPC-6治疗新诊断的胶质母细胞瘤的II期试验）。OSTR/STARS支持的一个关于T细胞进入脑肿瘤的项目正在进行中。

Although there have been advances in ways of how to overcome tumor related immunosuppression, many factors, such as T cell lymphopenia, T cell dysfunction, disproportionately high numbers of circulating suppressive regulatory T-lymphocytes, tumor cell expression of PD-L1, and a suppressive tumor-associated macrophage (TAM) orientation, as well as impaired immune effector trafficking across the BBB, present challenges for effective immunotherapy in glioblastoma. Our basic and translational research focuses on the immunologic interactions between brain tumors, the local tissue microenvironment, and the systemic immune response. We aim to enhancing immune therapies by 1) improving lymphocyte function and 2) making the tumor more susceptible to immune attack. We are interrogating components of the tumor microenvironment, such as immune modulating cells, hypoxia, and metabolic factors for their impact on immune function. We are also examining the mechanisms of immune depletion induced by corticosteroids and anti-cancer therapies. Finally, we are examining the epigenetic and molecular mechanisms employed by tumor cells to evade immune attack. The Immunology Program has two major components: Immunologic monitoring for immune-based brain tumor clinical trials and elucidating the mechanisms of immunosuppression in brain tumor patients focusing on iatrogenic causes such as corticosteroid use, lack of neoantigens and the impact of the tumor microenvironment. The immunologic monitoring will be performed as correlative biology for seminal brain tumor clinical trials, whereas the modulation of the immunosuppression in brain tumors will serve as the foundation for future, hypothesis-based clinical trials. In collaborate with NOB PTRF and Clinical Center, we are further investigating the experimental immunotherapeutics in vivo. Two clinical trials are then open recently (17C0102 Immune Checkpoint Inhibitor Nivolumab in People with Select Rare CNS Cancers; and 17C0034 Phase II trial of Radiation Therapy plus Temozolomide and Pembrolizumab with and without SPPC-6 in newly diagnosed Glioblastoma). One OSTR/STARS supported project on T cell trafficking into the brain tumor has been on-going.