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

2型免疫反应通常与屏障表面的寄生虫感染有关，而且 进化的部分原因是为了修复这些疾病造成的巨大组织损伤。然而，类型2的作用 免疫在癌症进展中的作用尚未得到充分研究，尽管许多癌症发生在粘膜表面。 准备好在受到组织侮辱时做出这样的反应。非小细胞肺癌(NSCLC)是 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非小细胞肺癌的治疗 但其疗效受到免疫抑制肿瘤微环境(TME)的限制 主要由各种髓系细胞亚群组成。使用单细胞RNA测序(scRNA-seq)，我们 最近绘制了人类和小鼠非小细胞肺癌TME的免疫图谱。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髓系细胞群体。在这两种情况下， 我们发现，TME内的髓系细胞特异性地上调了由IL-4驱动的转录程序， 典型的2型细胞因子。阻断IL-4对小鼠原位肺癌的保护作用。 令人惊讶的是，我们发现产生IL-4的Th2细胞基本上不存在于小鼠的肺TME和 人类。相反，IL-4几乎完全是由嗜碱性细胞产生的。因此，抗体介导的耗竭 体内嗜碱性粒细胞的存在大大减少了肺癌的发展。使用具有细胞类型特定缺失的小鼠 IL-4R研究发现，粒-单核细胞来源的细胞是主要的免疫细胞 应答IL-4以增加肿瘤负担。在肿瘤内，这些细胞中的绝大多数是 巨噬细胞和中性粒细胞。令人惊讶的是，我们还发现骨髓中的髓系祖细胞直接感觉到 IL-4/IL-13信号在肺癌发生发展中的作用此外，GMP特异性删除IL-4R的作用增强 髓系细胞分化对肺癌的反应，防止已知的所谓“紧急骨髓生成” 来刺激肿瘤的生长。 我们的中心假设是嗜碱性粒细胞衍生的IL-4通过控制NSCLC的发育和 免疫抑制髓系细胞的功能。为了解决这个问题，我们首先将识别来自肿瘤细胞的信号 激活嗜碱性粒细胞产生IL-4(目标1)。然后，我们将定义髓系固有的IL-4R信号如何 在TME和髓系分化水平上控制对非小细胞肺癌的免疫反应 在BM中，以及在PD-1免疫治疗期间这两个手臂如何协同作用(目标2)。最后，我们将整合我们的 FDA批准的IL-4R阻断药物杜匹单抗在小鼠系统中的首次临床试验结果 免疫治疗无效的转移性非小细胞肺癌患者的抗体检测及相关评价 免疫学改变。总而言之，我们的工作将(I)定义一个新的控制肺癌发展的轴，(Ii) 确定治疗干预的目标，以及(Iii)加强一个不断增长的范例，在这个范例中，肿瘤信号指示 发育中的髓系细胞的命运会影响癌症的结局。

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.