Immunoregulatory role of lung-resident club cell factors in lung cancer

摘要 尽管在手术、放疗和分子靶向治疗方面取得了进展，但非小细胞肺癌的死亡率仍然很低。 非小细胞肺癌（NSCLC）仍然很高。靶向PD-1/PD-1的免疫检查点抑制剂（ICI） L1轴已被批准用于治疗晚期NSCLC，但>70%的患者 由于肿瘤中存在多种免疫抑制屏障， 微环境（TME）。髓系抑制细胞在免疫系统中发挥有效的免疫抑制活性。 TME促进肿瘤进展，介导对免疫疗法的抗性，并赋予肿瘤细胞不良的免疫应答。 各种癌症类型的结果。我们已经证明，低剂量立体定向体部辐射 SBRT联合ICI可产生持久的抗肿瘤免疫力， 在NSCLC小鼠模型中的肿瘤消退和改善的存活率。出乎意料的是，我们发现 SBRT介导的肺驻留Scgb 1a 1+俱乐部细胞分泌组的激活是必要的， 提高ICI的疗效。我们鉴定了一组8种俱乐部细胞分泌因子， 与PD-1阻断剂的组合引起显著的肿瘤控制和改善的存活。 从机制上讲，俱乐部细胞因子抑制髓样抑制细胞，减少促肿瘤炎症反应， 调解员，以提高ICI的有效性。与临床前结果一致，NSCLC 对新辅助SBRT/ICI治疗有反应的患者显示血浆CC 10增加， 俱乐部细胞分泌体因子这些发现导致了俱乐部细胞因子 选择性抑制免疫抑制和骨髓抑制细胞的促炎功能， 提高免疫检查点阻断的效力。我们进一步假设俱乐部细胞因子 可以作为人NSCLC中SBRT/ICI治疗的反应和复发的生物标志物。 使用综合的临床前和临床方法，我们将通过两个测试这一假设 明确的目标。目的1将确定核心俱乐部细胞因子的确切身份， 它们减弱骨髓抑制细胞以产生持久抗肿瘤的机制 Aim 2将利用来自临床试验的样本来确定是否基于俱乐部细胞的免疫系统。 生物标志物与ICI/SBRT后的缓解治疗和转移复发相关 治疗人类NSCLC。这项工作将为开发一个基于机制的基本原理， 作为髓系抑制细胞的选择性抑制剂和用于提高功效的俱乐部细胞因子 ICI在NSCLC中

Abstract Despite advances in surgery, radiotherapy, and molecular targeted therapies, mortality in non-small cell lung cancer (NSCLC) remains high. Immune checkpoint inhibitors (ICI) targeting the PD-1/PD- L1 axis have been approved for the treatment of advanced NSCLC, yet >70% of the patients experience little clinical benefit due to a variety of immunosuppressive barriers in the tumor microenvironment (TME). Myeloid suppressor cells exert potent immunosuppressive activity in the TME that promotes tumor progression, mediates resistance to immunotherapy, and confers poor outcomes in a variety of cancer types. We have shown that low dose stereotactic body radiation therapy (SBRT) in combination with ICI confers durable anti-tumor immunity resulting in marked tumor regression and improved survival in mouse models of NSCLC. Unexpectedly, we uncovered that SBRT-mediated activation of lung resident Scgb1a1+ club cell secretome is necessary for improving the efficacy of ICI. We identified a set of 8 club cells secretory factors which in combination with PD-1 blockade elicited significant tumor control and improved survival. Mechanistically, club cell factors inhibit myeloid suppressor cells, reduce pro-tumor inflammatory mediators to improve the effectiveness of ICI. Consistent with the preclinical findings, NSCLC patients who responded to neoadjuvant SBRT/ICI therapy showed increased plasma CC10, a member of the club cell secretome factor. These findings have led to the hypothesis that club cell factors selectively inhibit immunosuppressive and proinflammatory function of myeloid suppressor cells to increase the efficacy of immune checkpoint blockade. We further hypothesize that club cell factors may serve as biomarkers of response and recurrence to SBRT/ICI therapy in human NSCLC. Using an integrated preclinical and clinical approach, we will test this hypothesis through two specific aims. Aim 1 will determine the exact identity of the core club cell factor/s and elucidate mechanisms by which they attenuate myeloid suppressor cells to generate durable anti-tumor immunity, and Aim 2 will leverage samples from a clinical trial to determine if club cell-based biomarkers are associated with response therapy and metastatic recurrence following ICI/SBRT therapy in human NSCLC. This work will develop a mechanism-based rationale for the development of club cell factors as selective inhibitors of myeloid suppressor cells and for improving the efficacy of ICI in NSCLC.