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

摘要-项目3 这个建议的主要目的是检查受体酪氨酸激酶的合作 Axl和MerTK作为免疫抑制性肿瘤免疫微环境（TIME）的驱动因子， 肿瘤Axl和MerTK同时可以将这种抑制性TIME（冷）转变为炎性TIME（热）。 免疫检查点抑制剂已获得FDA批准用于治疗头颈癌 （HNC）。尽管已经确定了获益，但临床试验强调，只有不到20%的HNC患者有反应， 这类很有前途的新型抑制剂这表明了知识的差距，并代表了一个主要的临床 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，最近的工作从 我们的实验室已经表明Axl和MerTK合作来驱动免疫学上的冷环境。在 此外，单独靶向肿瘤Axl或MerTK与靶向Axl和MerTK两者的一类新药相比， 同时，被称为INCB 081776，揭示了Axl和MerTK的双重靶向优于靶向Axl的上级 或单独使用MerTK。此外，INCB 081776有效地抑制肿瘤生长， 免疫活性小鼠，但不是在免疫缺陷小鼠，证明功能性免疫系统是 重要.用INCB 081776处理同基因模型与剂量相关的增加有关， 肿瘤浸润效应CD 4+和CD 8 + T细胞以及具有M1表型的巨噬细胞的百分比。 此外，INCB 081776降低了肿瘤内M2巨噬细胞和单核细胞髓样细胞的百分比。 衍生的抑制细胞（M-MDSC）免疫细胞群。总之，这表明同时瞄准 Axl和MerTK的组合在产生抗肿瘤（热）TIME方面是上级的。总的来说，我们的数据表明， Axl和MerTK一起工作以通过肿瘤内在和肿瘤外在（免疫）机制驱动HNC。我们 假设肿瘤Axl和MerTK通过调节协同产生骨髓抑制性TIME 同时靶向肿瘤Axl和MerTK的治疗策略将改变免疫介质的作用。 从冷到热的免疫时间导致更大的肿瘤杀伤。在目标1中，我们打算定义肿瘤Axl和Axl是如何与肿瘤细胞相互作用的。 MerTK通过招募髓源性细胞因子，协同调节促进这种冷时间的免疫介质 前体细胞和驱动M2极化，最终导致T细胞抑制。目标2： 确定在HNC同基因小鼠模型中同时靶向肿瘤Axl和MerTK的影响， 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， 我们建议进行一项临床试验，在患者中使用这种有前途的新药INCB 081776，并确定它是否可以改变 从冷的时间到热的时间，以及这是否会影响人类的肿瘤生长。为了进行这些研究， 组建了一支强大的分子生物学家团队，转化医学科学家，医学肿瘤学家，放射学 肿瘤学家、病理学家和生物统计学家。这一调查策略为翻译提供了很大的希望， 通过利用新的分子见解来解决HNC中存在的重大问题，为临床带来创新。

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.