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

了解显性免疫抑制性骨髓细胞反应在人类癌症中的作用和临床潜力

• 批准号: 10276957
• 负责人: Kurt A Schalper
• 金额: $ 38.32万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10276957
• 关键词: Animal Model; Area; Biological Markers; Biological Models; Blocking Antibodies; CTLA4 gene; Cells; Clinic; Clinical; Clinical Trials Design; Colorectal; Colorectal Cancer; Cytometry; Dependence; Development; Diagnostic; Drug or chemical Tissue Distribution; Effector Cell; Event; Exposure to; Genes; Glucose; Glycolysis; Human; Hypoxia; IL8 gene; IL8RA gene; IL8RB gene; Image; Immune; Immune Evasion; Immunity; Immunotherapeutic agent; Immunotherapy; Large Intestine Carcinoma; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Measures; Mediating; Metabolic; Modality; Molecular; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Outcome; Oxygen; PD-1/PD-L1; Pathology; Pathway interactions; Patient Selection; Patients; Property; Refractory; Resistance; Resources; Role; T cell response; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Thromboplastin; Translational Research; Tumor stage; Work; anti-tumor immune response; cancer immunobiology; cancer immunotherapy; carcinogenesis; clinically significant; colorectal cancer progression; deprivation; design; effector T cell; extracellular; immune checkpoint blockers; immunoregulation; lung Carcinoma; malignant phenotype; mortality; neutrophil; novel marker; novel therapeutics; optimal treatments; programmed cell death protein 1; receptor; response; rodent genome; sample collection; therapy resistant; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions

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.

肺癌和结直肠癌是三大最致命的恶性肿瘤之一， 约占所有癌症相关死亡的32%。虽然使用PD-1和CTLA-4阻断的抗癌免疫疗法 抗体显示出突出的活性，并已被批准用于多种肿瘤，大多数患者显示出 治疗抗性，并且在肿瘤类型之间的临床活性存在显著差异。目前 治疗敏感性/耐药性的决定因素以及显性免疫逃避作用的差异 癌症之间的通路是不确定的。为了大幅降低肺癌和结直肠癌的死亡率， 当务之急是：i）确定新的生物标志物，以最佳选择患者进行治疗; ii）发现 免疫疗法靶向PD-1/CTLA-4通路以外的靶点，可用于治疗难治性 iii）揭示免疫在肿瘤进展过程中的作用，以设计早期治疗干预。 我们小组最近的研究确定了IL-8/CXCR 1/CXCR 2通路作为阴性表达的强决定因素。 免疫调节和对免疫检查点阻断剂的治疗抗性。免疫抑制 IL-8通路的作用涉及肿瘤小生境中嗜中性粒细胞的增加和肿瘤局部的发展。 中性粒细胞胞外陷阱（NETs）。我们假设，IL-8通路的有害作用， 肿瘤免疫微环境通过局部代谢抑制而得到促进。我们预计这些反应 在具有不同免疫特性和对免疫检查点阻断剂敏感的肿瘤中， 肺癌和结肠直肠癌;以及在肿瘤发展的早期阶段。在这个项目中，通过3 互补的目标，我们将利用我们在癌症免疫生物学和转化研究的专业知识：i） 确定IL-8通路和骨髓细胞应答的代谢/免疫背景和生物标志物值 ii）分析IL-8诱导的NET形成作为负性免疫调节因子的机制和作用; iii）检查IL-8途径和免疫结构在人恶性肿瘤中的作用， 致癌作用和早期癌症进展。这项工作的成果将加速研究成果的转化 将概念引入临床，以建立新的生物标志物，支持临床试验和设计的解释 为早期和晚期肿瘤提供最佳治疗方式。