Translational Immunology

尽管在克服肿瘤相关免疫抑制的方法上取得了进展，但许多因素，如T细胞减少，T细胞功能障碍，循环中高水平的循环抑制调节性T淋巴细胞，肿瘤细胞PD-L1的表达，肿瘤相关巨噬细胞()的抑制取向，以及免疫效应器跨血脑屏障的运输受损，给胶质母细胞瘤的有效免疫治疗带来了挑战。我们的基础和翻译研究集中在脑肿瘤、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加强免疫治疗。我们正在询问肿瘤微环境的组成部分，如免疫调节细胞、缺氧和代谢因素，以了解它们对免疫功能的影响。我们还在研究皮质类固醇和抗癌治疗导致免疫衰竭的机制。最后，我们正在研究肿瘤细胞用来逃避免疫攻击的表观遗传学和分子机制。免疫学计划包括两个主要部分：基于免疫的脑肿瘤临床试验的免疫监测，以及阐明脑肿瘤患者免疫抑制的机制，重点是皮质类固醇的使用、新抗原的缺乏和肿瘤微环境的影响等医源性原因。免疫学监测将作为种子脑瘤临床试验的相关生物学，而脑瘤免疫抑制的调节将为未来基于假设的临床试验奠定基础。在与NOB PTRF和临床中心的合作下，我们正在进一步研究体内的实验性免疫疗法。最近开始了两项临床试验(17C0102免疫检查点抑制剂Nivolumab用于罕见的中枢神经系统癌症患者；17C0034放射治疗加替莫唑胺和培布罗珠单抗加或不加SPPC-6治疗新诊断的胶质母细胞瘤)。一项由OSTR/STARS资助的关于T细胞向脑瘤转移的项目正在进行中。

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.