Project 3: Modulation of the head and neck tumor immune microenvironment by targeting the TAM family of receptors

摘要--项目3 这项建议的主要目的是研究受体酪氨酸激酶的协同作用。 AXL和MerTK作为免疫抑制肿瘤免疫微环境(TIME)的驱动因子和IF靶向 肿瘤AXL和MerTK同时可以将这种抑制时间(冷)转变为炎症时间(热)。 免疫检查点抑制剂已获得FDA批准用于头颈部癌症的治疗 (HNC)。尽管已经确立了益处，但临床试验强调，只有不到20%的HNC患者有反应 这类前景看好的新型抑制剂。这表明了知识上的差距，并代表了一个重大的临床 当我们试图了解如何最好地增强免疫系统以获得更好的结果时，我们就会遇到障碍。最近的工作来自 我们的实验室已经证明，Axl和MerTK合作推动了免疫寒冷的环境。在……里面 此外，单独靶向肿瘤AXL或MerTK与同时靶向AXL和MerTK的新型药物相比 同时，被称为INCB081776的研究表明，AXL和MerTK的双重靶向优于靶向AXL 或者在免疫模型中单独使用MerTK。此外，INCB081776有效地抑制了肿瘤的生长 免疫功能正常的小鼠，但在免疫缺陷的小鼠中不存在，证明了功能免疫系统是 很重要。用INCB081776治疗同基因模型与剂量相关的增加有关 肿瘤浸润性效应细胞CD4+和CD8+T细胞以及具有M1表型的巨噬细胞的百分比。 此外，INCB081776还降低了瘤内M2巨噬细胞和单核细胞髓样细胞的百分比。 衍生抑制细胞(M-MDSC)免疫细胞群。总而言之，这表明同时瞄准 在产生抗肿瘤(热)时间方面优于AXL和MerTK。总而言之，我们的数据表明肿瘤 AXL和MerTK通过肿瘤内源性和外源性(免疫)机制共同驱动HNC。我们 假设肿瘤Ax1和MerTK通过调节共同产生髓系抑制时间 同时针对肿瘤Ax1和MerTK的治疗策略将改变 从冷到热的免疫时间导致更大的肿瘤杀伤力。在目标1中，我们打算定义肿瘤Ax1和 MerTK合作调节免疫介质，通过招募髓系来源的细胞来促进这一寒冷时期 前体细胞和驱动M2极化最终导致T细胞抑制。在目标2中，我们打算 确定同时靶向肿瘤Axl和MerTK对HNC同基因小鼠模型和 测量对免疫细胞浸润(巨噬细胞和T细胞)和肿瘤生长的影响。最后，在目标3中， 我们提出了一项临床试验，在患者中使用这种有前景的新药INCB081776，并确定它是否可以 从冷的时候到热的时候，如果这会影响人类的肿瘤生长。为了进行这些研究，我们有 组建了一支由分子生物学家、转化内科科学家、内科肿瘤学家、放射专家组成的强大团队 肿瘤学家、病理学家和生物统计学家。这一调查策略为翻译到 并通过利用新的分子洞察力来解决HNC中存在的重大问题，从而带来创新。

ABSTRACT – PROJECT 3 The primary objective of this proposal is to examine the cooperation of the receptor tyrosine kinases Axl and MerTK as drivers of an immunosuppressive tumor immune microenvironment (TIME) and if targeting tumor Axl and MerTK simultaneously can turn this suppressive TIME (cold) to an inflammatory TIME (hot). Immune checkpoint inhibitors have gained FDA approval in the management of Head and Neck Cancer (HNC). Despite established benefit, clinical trials have highlighted that less than 20% of HNC patients respond to this promising new class of inhibitors. This suggests a gap in knowledge and represents a major clinical hurdle as we try to understand how best to enhance the immune system to better outcomes. Recent work from our laboratory has shown that Axl and MerTK cooperate to drive an immunologically cold environment. In addition, targeting tumor Axl or MerTK individually versus a new class of drug that targets both Axl and MerTK simultaneously, called INCB081776, revealed that dual targeting of Axl and MerTK was superior to targeting Axl or MerTK alone in immune models. Furthermore, INCB081776 potently inhibited tumor growth in immunocompetent mice but not in immunodeficient mice, demonstrating that a functional immune system is important. Treatment of syngeneic models with INCB081776 was associated with dose-related increases in the percentage of tumor-infiltrating effector CD4+ and CD8+ T cells as well as macrophages with the M1 phenotype. In addition, INCB081776 decreased the percentage of intratumoral M2 macrophages and monocytic myeloid– derived suppressor cell (M-MDSC) immune cell populations. Together, this suggests that simultaneous targeting of Axl and MerTK is superior in producing an anti-tumor (hot) TIME. Collectively, our data suggests that tumor Axl and MerTK work together to drive HNC via tumor intrinsic and tumor extrinsic (immune) mechanisms. We hypothesize that tumor Axl and MerTK cooperate to produce a myeloid-suppressive TIME, through regulation of immune mediators, and that therapeutic strategies targeting tumor Axl and MerTK simultaneously will shift the immune TIME from cold to hot resulting in greater tumor kill. In Aim 1 we intend to define how tumor Axl and MerTK cooperate to regulate immune mediators that promote this cold TIME by recruiting myeloid derived precursor cells and driving M2 polarization ultimately leading to T cell suppression. In Aim 2 we intend to determine the impact of targeting tumor Axl and MerTK simultaneously in HNC syngeneic mouse models and measure the impact on immune cell infiltration (Macrophages and T cells) and tumor growth. Finally, in Aim 3, we propose a clinical trial to utilize this promising new drug, INCB081776, in patients and determine if it can shift a cold TIME to a hot TIME and if this impacts tumor growth in humans. To carry out these studies we have assembled a strong team of molecular biologists, translational physician-scientists, medical oncologist, radiation oncologist, pathologists and biostatisticians. This investigative strategy holds great promise for translation to the clinic and brings innovation by leveraging new molecular insights to a significant existing problem in HNC.