Understanding the role and clinical potential of dominant immune suppressive myeloid-cell responses in human cancer

肺癌和结直肠癌是最致命的三种恶性肿瘤之一，它们加在一起占 约占所有癌症相关死亡人数的32%。尽管使用PD-1和CTLA-4封闭的抗癌免疫治疗 大多数患者显示，抗体显示出显著的活性，并已被批准用于多种肿瘤 治疗耐药和临床活动性在不同肿瘤类型之间存在显著差异。目前， 治疗敏感性/耐药性的决定因素和显性免疫逃避作用的差异 跨越癌症的途径是不确定的。为了大幅降低肺癌和结直肠癌的死亡率， 当务之急：一)为最佳选择患者治疗确定新的生物标记物；二)发现 PD-1/CTLA-4通路以外的免疫治疗靶点可能用于治疗难治性白血病患者 以及iii)揭示免疫在肿瘤进展中的作用，以设计早期治疗干预措施。 本课题组最近的研究发现，IL-8/CXCR1/CXCR2通路是阴性的强烈决定因素 对免疫检查点阻滞剂的免疫调节和治疗抵抗。免疫抑制 IL-8途径的作用涉及肿瘤巢内中性粒细胞的增加和局部肿瘤的发展。 中性粒细胞胞外陷阱(NETs)。我们假设，IL-8途径在人卵巢癌中的有害作用 局部代谢抑制促进了肿瘤免疫微环境的形成。我们期待着这些回应 不同的肿瘤具有不同的免疫特性和对免疫检查点阻滞剂的敏感性 肺癌和结直肠癌；以及在肿瘤发展的早期阶段。在这个项目中和通过3 相辅相成的目标，我们将利用我们在癌症免疫生物学和翻译研究方面的专业知识：i) 确定IL-8途径和髓系细胞反应的代谢/免疫环境和生物标记物价值 在癌症中的作用；II)分析IL-8诱导的网络形成作为负免疫调节的机制和作用 事件在人类恶性肿瘤中的作用；以及iii)检测IL-8途径和免疫环境在 癌症的发生和癌症的早期进展。这项工作的结果将加快研究成果的翻译 概念进入临床以建立新的生物标记物，支持临床试验和设计的解释 早期和晚期肿瘤的最佳治疗方式。

Lung and colorectal cancer are among the top three most deadly malignancies and together they account for ~32% of all cancer-related fatalities. Although anti-cancer immunotherapy using PD-1 and CTLA-4 blocking antibodies shows prominent activity and has been approved for use in multiple tumors, most patients show treatment resistance and there are striking differences in the clinical activity across tumor types. Currently, the determinants for treatment sensitivity/resistance and the difference in the role of dominant immune evasion pathways across cancers are uncertain. To substantially reduce lung and colorectal cancer mortality, it is imperative to: i) Identify novel biomarkers for optimal selection of patients for treatment; ii) Uncover immunotherapy targets beyond the PD-1/CTLA-4 pathways that may serve to treat patients with refractory tumors; and iii) Reveal the role of immunity during tumor progression to design early therapeutic interventions. Recent studies from our group identified the IL-8/CXCR1/CXCR2 pathway as a strong determinant for negative immune modulation and therapeutic resistance to immune checkpoint blockers. The immune suppressive effects of the IL-8 pathway involve increased neutrophils in the tumor niche and local development of neutrophil extracellular traps (NETs). We hypothesize that the deleterious effects of the IL-8 pathway in the tumor immune microenvironment are promoted by local metabolic suppression. We anticipate these responses to be different in tumors with distinct immune properties and sensitivity to immune checkpoint blockers such as lung and colorectal cancer; and during early stages of tumor development. In this project and through 3 complementary aims, we will leverage our expertise in cancer immunobiology and translational research to: i) Determine the metabolic/immune context and biomarker value of the IL-8 pathway and myeloid-cell responses in cancer; ii) Analyze the mechanisms and role of IL-8 induced NET formation as negative immunomodulatory event in human malignancies; and iii) Examine the role of the IL-8 pathway and immune contexture in carcinogenesis and early cancer progression. The results from this work will accelerate translation of research concepts into the clinic for establishment of novel biomarkers, support interpretation of clinical trials and design optimal treatment modalities for early-stage and advanced tumors.