A Novel ULK1 Pathway as a New Therapeutic Target in Melanoma

项目总结/摘要 黑色素瘤是一种高度致命的恶性肿瘤，免疫治疗方法已被证明是有效的。 虽然免疫检查点阻断（ICB）已经改变了晚期黑色素瘤的治疗，但大多数 患者最初对治疗有抵抗力或有反应但随后复发。因此，努力查明 对检查点抑制剂的抗性和克服原发性和获得性抗性的方法是必要的。 令人惊讶的是，II型干扰素（IFN β）信号传导途径和IFN刺激基因（ISG）的表达在小鼠中的表达与IFN β的表达相关。 黑色素瘤患者已被证明与ICB治疗的反应或抗性相关， context-dependent方式。虽然IFN γ诱导的基因是肿瘤反应性T细胞的效应子功能所必需的， 在黑色素瘤中，IFN γ还已知诱导免疫抑制基因的表达， 慢性IFN γ信号传导促进对ICB的获得性抗性。IFN γ信号的这种双重作用支持了 需要确定选择性调节其作用的方法，以促进细胞毒性T淋巴细胞（CTL）活性 而不促进免疫抑制。我们最近发现ULK 1（Unc-51样激酶1）控制着 独特的IFN γ信号传导事件的激活和特异性IFN γ诱导的基因的转录参与控制 免疫反应。重要的是，我们的初步研究表明，ULK 1的遗传或药理学靶向 在黑色素瘤细胞中抑制IFN γ诱导的免疫抑制基因的表达，而不影响表达 高水平的ULK 1表达与黑色素瘤的生存率低相关 患者该项目的目标是确定是否靶向ULK 1阻断IFN γ依赖性免疫抑制 作用和相关的生物学应答，同时促进IFN γ介导的抗黑素瘤的CTL活性。要求1 将确定ULK 1对IFN γ诱导的免疫抑制基因表达和细胞毒性的特异性作用。 T淋巴细胞抗黑色素瘤活性。它包括产生特定的敲除黑色素瘤细胞， 体外评价ULK对T细胞介导的肿瘤杀伤的抑制。目标2将定义ULK 1在ICB中的作用- 介导的免疫反应。基因或细胞因子对黑色素瘤生长的影响 将在体内检查与免疫检查点抑制剂组合的ULK 1的药理学抑制。 此外，ULK 1的表达和活化将与黑色素瘤患者的临床反应相关 接受ICB治疗。该项目的结果将推进我们对特定IFN γ信号传导如何 这些事件影响针对黑色素瘤的免疫应答的成功，并将为新的靶向治疗提供基础。 涉及IFN γ信号传导的特异性调节剂与免疫检查点抑制剂组合的方法， 黑色素瘤的治疗

Project Summary/Abstract Melanoma is a highly fatal malignancy for which immunotherapy approaches have been shown to be effective. While immune checkpoint blockade (ICB) has transformed the treatment of advanced melanoma, the majority of patients are resistant to therapy initially or respond but then relapse. Thus, efforts to identify mechanisms of resistance to checkpoint inhibitors and approaches to overcome primary and acquired resistance are warranted. Surprisingly, type II interferon (IFN) signaling pathways and expression of IFN-stimulated genes (ISGs) in melanoma patients have been shown to correlate with either response or resistance to ICB treatment, in a context-dependent manner. While IFN-inducible genes are required for effector function of tumor-reactive T cells and response to ICB in melanoma, IFN is also known to induce expression of immunosuppressive genes and chronic IFN signaling promotes acquired resistance to ICB. This dual role of IFN signaling supports the need to identify means to selectively regulate its effects in order to promote cytotoxic T lymphocyte (CTL) activity without promoting immunosuppression. We have recently discovered that ULK1 (Unc-51-like kinase 1) controls activation of unique IFN signaling events and transcription of specific IFN-induced genes involved in the control of immune responses. Importantly, our preliminary studies show that genetic or pharmacologic targeting of ULK1 in melanoma cells represses IFN-induced expression of immunosuppressive genes without affecting expression of immunostimulatory ones, and high levels of ULK1 expression correlate with poor survival in melanoma patients. The goal of this project is to determine if targeting ULK1 blocks IFN-dependent immunosuppressive effects and related biological responses, while promoting IFN-mediated CTL activity against melanoma. Aim 1 will define the specific role of ULK1 on IFN-induced expression of immunosuppressive genes and on cytotoxic T lymphocyte activity against melanoma. It includes generation of specific knockout melanoma cells, and evaluation of ULK inhibition on T-cell mediated tumor killing in vitro. Aim 2 will define the role of ULK1 in ICB- mediated immune responses in melanoma. The effects on melanoma tumor growth of genetic or pharmacological inhibition of ULK1 in combination with immune checkpoint inhibitors will be examined in vivo. Additionally, the expression and activation of ULK1 will be correlated to clinical responses in melanoma patients receiving ICB therapy. The results of this project will advance our understanding on how specific IFN signaling events affect the success of immune responses against melanoma and will provide the basis for novel targeted approaches involving combination of specific regulators of IFN signaling with immune checkpoint inhibitors for the treatment of melanoma.