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

摘要 尽管在手术、放射治疗和分子靶向治疗方面取得了进展，但在 细胞肺癌(NSCLC)的发病率仍然居高不下。针对PD-1/PD-1的免疫检查点抑制物(ICI) L1轴已被批准用于晚期非小细胞肺癌的治疗，但70%的患者 由于肿瘤中存在多种免疫抑制屏障，临床获益甚微 微环境(TME)。髓系抑制细胞在骨髓瘤中发挥强大的免疫抑制活性 TME促进肿瘤进展，调节免疫治疗的抵抗，并导致不良反应 在各种癌症类型中的结果。我们已经证明了低剂量的立体定向身体辐射 治疗(SBRT)与ICI相结合可提供持久的抗肿瘤免疫，导致显著 小鼠非小细胞肺癌模型的肿瘤消退和生存改善。出乎意料的是，我们发现 SBRT介导的肺常驻Scgb1a1+俱乐部细胞分泌体的激活对 提高ICI的疗效。我们鉴定了一组8个俱乐部细胞分泌因子，它们在 联合使用PD-1阻滞剂可显著控制肿瘤并提高存活率。 从机制上讲，俱乐部细胞因子抑制髓系抑制细胞，减少促肿瘤炎症 调解员，以提高ICI的有效性。与临床前研究结果一致，非小细胞肺癌 对新辅助SBRT/ICI治疗有反应的患者显示血浆CC10升高，其成员 俱乐部细胞分泌因子。这些发现导致了一种假设，即俱乐部细胞因子 选择性抑制髓系抑制细胞的免疫抑制和促炎功能 提高免疫检查点封锁的效果。我们进一步假设，俱乐部细胞因子 可作为非小细胞肺癌患者对SBRT/ICI治疗反应和复发的生物标志物。 使用临床前和临床相结合的方法，我们将通过以下两种方法来检验这一假设 明确的目标。目标1将确定核心俱乐部细胞因子的确切身份/S并澄清 它们弱化髓系抑制细胞产生持久抗肿瘤作用的机制 免疫力，Aim 2将利用临床试验的样本来确定基于俱乐部细胞的 生物标记物与ICI/SBRT后的反应治疗和转移复发相关 人类非小细胞肺癌的治疗。这项工作将为发展建立一个基于机制的理论基础 俱乐部细胞因子作为髓系抑制细胞的选择性抑制剂和提高疗效的研究 ICI在非小细胞肺癌中的表达。

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.