Neutrophil derived proteinases abolish the IFNG signature in NSCLC

中性粒细胞衍生的蛋白酶消除 NSCLC 中的 IFNG 特征

• 批准号: 10717448
• 负责人: A McGarry Houghton
• 金额: $ 57.31万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-07 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717448
• 关键词: Accounting; Activated Lymphocyte; Antibody Therapy; Beds; Biological Assay; Bone Marrow; CD8-Positive T-Lymphocytes; CD8B1 gene; CXC chemokine receptor 3; CXCL10 gene; CXCL9 gene; CXCR3 gene; Cancer Etiology; Cancer Patient; Cathepsin G; Cell surface; Cells; Cessation of life; Chemotaxis; Clinical; Clinical Trials; Cytoplasmic Granules; Data; Dendritic Cells; Event; Failure; Feedback; Fluorescent in Situ Hybridization; Genes; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunohistochemistry; Immunotherapy; In Vitro; Infiltration; Interferon Type II; Leukocyte Elastase; Link; Lung Neoplasms; Lymphocyte; Lymphocyte Function; MMP8 gene; MMP9 gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Modeling; Mus; Myelogenous; Myeloid-derived suppressor cells; Neutrophil Collagenase; Neutrophil Infiltration; Non-Small-Cell Lung Carcinoma; Outcome; PD-1/PD-L1; Peptide Hydrolases; Predictive Factor; Process; Production; Property; Protease Inhibitor; Proteinase 3; Proteins; Reporting; Signal Transduction; Site; Source; Surface; System; T cell infiltration; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Thinking; Treatment outcome; Tumor-associated macrophages; Work; anti-PD-1; anti-PD-L1; anti-PD-L1 therapy; cell type; checkpoint therapy; chemokine; chemokine receptor; cohort; cytokine; exhaust; immune checkpoint; improved; in vivo; inhibitor; mouse model; mutant; neoplastic cell; neutrophil; novel; proteinase In; recruit; response; success; treatment response; tumor; tumor microenvironment

ABSTRACT Although immune checkpoint inhibitor (ICI) therapy has been a tremendous clinical success, just ~20% of non- small cell lung cancer (NSCLC) patients respond to anti-PD1/PDL1 therapy. The two major factors predictive of favorable treatment response to ICI therapy are the presence of the IFNG signature and evidence of CD8+ T cell infiltration into malignant tumor. Work from our group has shown that neutrophil infiltrated non-small cell lung cancers do not display the IFNG signature, do not display CD8+ infiltration into malignant tumor, and do not respond to ICI treatment. Our hypothesis to explain these observations is that tumor-associated neutrophils release proteinases that degrade key cytokines (IFNG), chemokines (CXCL-9, -10, -11) and a chemokine receptor (CXCR3) that destroys the IFNG mediated chemotactic gradient that facilitates T cell infiltration into tumors. The proposed studies will demonstrate that a number of key neutrophil-derived proteinases are capable of degrading T cell recruiting chemokines and CXCR3 and identify the novel cleavage products resulting from these events. The functional consequences of these proteolytic events will be demonstrated in novel multicellular tumor-in-chip systems and in state-of-the art mouse models of lung cancer. Lastly, we will employ a combined fluorescent in-situ hybridization (FISH) and multiplexed immunohistochemistry (M-IHC) panel to study the relationship between CXCL9 expressing tumor cells, infiltrating CD8+CXCR3+ T cells, and TAN and determine the impact that these measures have on ICI treatment outcomes in NSCLC patients.

摘要 虽然免疫检查点抑制剂（ICI）治疗已经取得了巨大的临床成功，但只有约20%的非免疫检查点抑制剂治疗。 小细胞肺癌（NSCLC）患者对抗PD 1/PDL 1治疗有反应。两个主要的预测因素 对ICI治疗有利的治疗反应是IFNG标记的存在和CD 8 + T细胞的证据， 恶性肿瘤浸润。我们小组的工作表明，中性粒细胞浸润的非小细胞肺 癌症不显示IFNG标记，不显示CD 8+浸润到恶性肿瘤中，并且不 对ICI治疗有反应。我们解释这些观察结果的假设是，肿瘤相关中性粒细胞 释放降解关键细胞因子（IFNG）、趋化因子（CXCL-9、-10、-11）和趋化因子的蛋白酶 受体（CXCR 3），破坏IFNG介导的趋化梯度，促进T细胞浸润到 肿瘤的拟议的研究将证明，一些关键的嗜中性粒细胞衍生的蛋白酶能够 降解T细胞募集趋化因子和CXCR 3，并确定由 这些事件。这些蛋白水解事件的功能后果将在新的多细胞生物学中得到证实。 肿瘤芯片系统和最先进的肺癌小鼠模型。最后，我们将使用一个组合 荧光原位杂交（FISH）和多重免疫组织化学（M-MHC）面板来研究 表达CXCL 9的肿瘤细胞、浸润性CD 8 + CXCR 3 + T细胞和TAN之间的关系， 这些措施对NSCLC患者ICI治疗结局的影响。