Type 2 immunity: a primitive response to epithelial injury that shapes bone marrow and lung myeloid crosstalk

2型免疫：对上皮损伤的原始反应，形成骨髓和肺髓细胞串扰

• 批准号: 10577950
• 负责人: MIRIAM MERAD
• 金额: $ 65.83万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-02 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577950
• 关键词: Address; Affect; Allergic Disease; Antibodies; Antigen-Antibody Complex; Basophils; Biopsy Specimen; Blocking Antibodies; Blood specimen; Bone Marrow; Cancer Etiology; Cancer Patient; Caring; Cell Differentiation process; Cell physiology; Cells; Cessation of life; Chimera organism; Clinical Trials; Coculture Techniques; Coupled; Cre driver; Cues; Cytokine Signaling; Data; Dendritic Cells; Development; Disease; Emergency Situation; Epithelium; Exhibits; Experimental Models; FDA approved; Gene Expression Profile; Generations; Genetic; Genetic Transcription; Grant; Human; Immune; Immune response; Immunity; Immunologics; Immunophenotyping; Immunosuppression; Immunotherapy; Infiltration; Interleukin 4 Receptor; Interleukin-13; Interleukin-4; Lesion; Leucocytic infiltrate; Location; Lung; Lung Adenocarcinoma; Lung Neoplasms; Macrophage; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Measures; Mediating; Minority; Molecular; Mucous Membrane; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Myelopoiesis; Non-Small-Cell Lung Carcinoma; Outcome; PD-1 blockade; PD-L1 blockade; Parasitic infection; Pathway interactions; Patients; Population; Population Heterogeneity; Production; Reagent; Receptor Signaling; Refractory; Regulation; Relapse; Role; Shapes; Signal Transduction; Site; Source; Spatial Distribution; Structure of parenchyma of lung; Surface; System; Testing; Th2 Cells; Therapeutic Equivalency; Therapeutic Intervention; Tissues; Tumor Burden; Tumor Immunity; Tumor Tissue; Unresectable; Work; anti-PD1 antibodies; anti-tumor immune response; arm; cell type; cytokine; design; effective therapy; epigenomics; epithelial injury; granulocyte-monocyte progenitors; high dimensionality; imprint; in vivo; lung lesion; monocyte; mouse model; multiplexed imaging; myeloid cell development; neoplastic cell; neutrophil; novel; prevent; progenitor; programs; receptor; repaired; response; restraint; single-cell RNA sequencing; stem cells; synergism; targeted treatment; transcriptomics; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions

Type 2 immune responses are classically associated with parasite infections at barrier surfaces, and evolved in part to repair the massive tissue damage that these maladies induce. However, the role of Type 2 immunity in cancer progression is understudied, despite the fact that many cancers occur at mucosal surfaces that are primed to engage such responses upon tissue insult. Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide. PD-(L)1 immunotherapy has revolutionized care for NSCLC patients, but its efficacy is limited by the immunosuppressive tumor microenvironment (TME) which is predominantly populated by various myeloid cell subsets. Using single cell RNA-sequencing (scRNA-seq), we recently mapped the immune landscape of the human and murine NSCLC TME. We identified several newfound populations of myeloid cells that exhibited high transcriptional concordance across species. In both instances, we found that myeloid cells within the TME specifically upregulated a transcriptional program driven by IL-4, a prototypical Type 2 cytokine. Blockade of IL-4 strongly protected mice against orthotopic lung tumors. Surprisingly, we found that IL-4-producing Th2 cells were essentially absent from the lung TME in mice and humans. Instead, IL-4 was almost exclusively produced by basophils. Accordingly, antibody-mediated depletion of basophils in vivo strongly reduced lung tumor development. Using mice with cell type-specific deletion of the IL-4R we found that granulocyte-monocyte progenitor (GMP)-derived cells were the dominant immune cells responding to IL-4 to enhance tumor burden. Within the tumor, the overwhelming majority of these cells are macrophages and neutrophils. Surprisingly, we also discovered that myeloid progenitors in BM directly sense IL-4/IL-13 signaling during lung tumor development. Furthermore, GMP-specific deletion of IL-4R enhanced myeloid cell differentiation in response to lung tumors, preventing the so-called “emergency myelopoiesis” known to fuel tumor growth. Our central hypothesis is that basophil-derived IL-4 promotes NSCLC by controlling the development and function of immunosuppressive myeloid cells. To address this, we first will identify signals from neoplastic cells that activate basophils to produce IL-4 (Aim 1). Then, we will define how myeloid-intrinsic IL-4R signaling controls the immune response to NSCLC, both at the level of the TME and at the level of myeloid differentiation in BM, and how these two arms synergize during PD-1 immunotherapy (Aim 2). Finally, we will integrate our findings from murine systems into the first human clinical trial of dupilumab, an FDA-approved IL-4R blocking antibody, in metastatic NSCLC patients who have not responded to immunotherapy and evaluate relevant immunologic alterations. Collectively, our work will (i) define a novel axis controlling lung tumor development, (ii) identify targets for therapeutic intervention, and (iii) reinforce a growing paradigm in which tumor signals instruct the fates of developing myeloid cells to affect cancer outcome.

2型免疫应答通常与屏障表面的寄生虫感染相关， 部分是为了修复这些疾病引起的大规模组织损伤。2型的作用 尽管许多癌症发生在粘膜表面，但癌症进展中的免疫性研究不足 其被准备好在组织损伤时进行这样的反应。非小细胞肺癌（NSCLC）是 全球癌症相关死亡的主要原因。PD-（L）1免疫疗法彻底改变了NSCLC的护理 患者，但其疗效受到免疫抑制性肿瘤微环境（TME）的限制， 主要由各种骨髓细胞亚群构成。使用单细胞RNA测序（scRNA-seq），我们 最近绘制了人类和小鼠NSCLC TME的免疫景观。我们发现了几个新发现的 在不同物种间表现出高转录一致性的骨髓细胞群体。在这两种情况下， 我们发现，TME内的髓样细胞特异性上调由IL-4驱动的转录程序， 原型2型细胞因子。IL-4的阻断强烈保护小鼠免受原位肺肿瘤的侵害。 令人惊讶的是，我们发现小鼠肺TME中基本上不存在产生IL-4的Th 2细胞， 人类相反，IL-4几乎完全由嗜碱性粒细胞产生。因此，抗体介导的消耗 体内嗜碱性粒细胞的减少强烈地降低了肺肿瘤的发展。使用具有细胞类型特异性缺失的小鼠， IL-4 R检测发现，粒细胞-单核细胞祖细胞（GMP）源性细胞是主要的免疫细胞 响应IL-4以增强肿瘤负荷。在肿瘤内，绝大多数这些细胞是 巨噬细胞和嗜中性粒细胞。令人惊讶的是，我们还发现，骨髓中的髓系祖细胞直接感知 肺肿瘤发展过程中的IL-4/IL-13信号传导。此外，GMP特异性的IL-4 R缺失增强了IL-4 R的表达。 骨髓细胞分化对肺肿瘤的反应，防止所谓的“紧急骨髓”已知 促进肿瘤生长 我们的中心假设是，嗜碱性粒细胞来源的IL-4通过控制NSCLC的发展， 免疫抑制骨髓细胞的功能。为了解决这个问题，我们首先将识别来自肿瘤细胞的信号 其激活嗜碱性粒细胞以产生IL-4（Aim 1）。然后，我们将定义骨髓内源性IL-4 R信号转导是如何 在TME水平和髓系分化水平控制对NSCLC的免疫应答 在BM中，以及这两个臂在PD-I免疫治疗期间如何协同作用（目的2）。最后，我们将整合我们的 将小鼠系统的发现纳入dupilumab（FDA批准的IL-4 R β阻断剂）的首次人体临床试验 抗体，在对免疫治疗无应答的转移性NSCLC患者中， 免疫改变总的来说，我们的工作将（i）定义一个控制肺肿瘤发展的新轴，（ii） 确定治疗干预的靶点，以及（iii）加强肿瘤信号指示 发展中的骨髓细胞的命运影响癌症的结果。