肿瘤引流淋巴结在联合免疫治疗和放疗的远隔效应中的关键作用。
Pivotal roles of tumor-draining lymph nodes in the abscopal effects from combined immunotherapy and radiotherapy.
机构信息
Department of Oncology, Shandong University Cancer Center, Jinan, Shandong, 250117, P. R. China.
Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, P. R. China.
出版信息
Cancer Commun (Lond). 2022 Oct;42(10):971-986. doi: 10.1002/cac2.12348. Epub 2022 Aug 13.
BACKGROUND
Currently, due to synergy enhancement of anti-tumor effects and potent stimulation of abscopal effects, combination therapy with irradiation and programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint inhibition (immuno-radiotherapy, iRT) has revolutionized the therapeutic guidelines. It has been demonstrated that tumor-draining lymph nodes (TDLN) are essential for effective antitumor immunity induced by radiotherapy, immunotherapy, or iRT. Given that the function of TDLN in iRT remains unclear, this study aimed to investigate the function and mechanism of TDLN in iRT-induced abscopal effects.
METHODS
The function of TDLN was evaluated using unilateral or bilateral MC38 and B16F10 subcutaneous tumor models with or without indicated TDLN. The flow cytometry, multiple immunofluorescence analysis, and NanoString analysis were utilized to detect the composition and function of the immune cells in the primary and abscopal tumor microenvironment. Additionally, we tempted to interrogate the possible mechanisms via RNA-sequencing of tumor-infiltrating lymphocytes and TDLN.
RESULTS
TDLN deficiency impaired the control of tumor growth by monotherapy. Bilateral TDLN removal rather than unilateral TDLN removal substantially curtailed iRT-stimulated anti-tumor and abscopal effects. Furthermore, in the absence of TDLN, the infiltration of CD45 and CD8 T cells was substantially reduced in both primary and abscopal tumors, and the anti-tumor function of CD8 T cells was attenuated as well. Additionally, the polarization of tumor-associated macrophages in primary and abscopal tumors were found to be dependent on intact bilateral TDLN. RNA-sequencing data indicated that impaired infiltration and anti-tumor effects of immune cells partially attributed to the altered secretion of components from the tumor microenvironment.
CONCLUSIONS
TDLN play a critical role in iRT by promoting the infiltration of CD8 T cells and maintaining the M1/M2 macrophage ratio.
背景
目前，由于抗肿瘤作用的协同增强和强烈刺激远隔效应，联合放疗和程序性细胞死亡蛋白 1/程序性死亡配体 1（PD-1/PD-L1）免疫检查点抑制（免疫放疗，iRT）的治疗已彻底改变了治疗指南。已经证明，引流肿瘤的淋巴结（TDLN）对于放疗、免疫治疗或 iRT 诱导的有效抗肿瘤免疫至关重要。鉴于 TDLN 在 iRT 中的功能尚不清楚，本研究旨在探讨 TDLN 在 iRT 诱导的远隔效应中的作用和机制。
方法
使用单侧或双侧 MC38 和 B16F10 皮下肿瘤模型，评估 TDLN 的功能，这些模型具有或不具有指示性 TDLN。使用流式细胞术、多重免疫荧光分析和 NanoString 分析检测原发性和远隔肿瘤微环境中免疫细胞的组成和功能。此外，我们试图通过肿瘤浸润淋巴细胞和 TDLN 的 RNA 测序来探究可能的机制。
结果
TDLN 缺失会削弱单一疗法控制肿瘤生长的能力。双侧 TDLN 切除而非单侧 TDLN 切除大大削弱了 iRT 刺激的抗肿瘤和远隔效应。此外，在没有 TDLN 的情况下，原发性和远隔肿瘤中 CD45 和 CD8 T 细胞的浸润显著减少，CD8 T 细胞的抗肿瘤功能也减弱。此外，发现原发性和远隔肿瘤中肿瘤相关巨噬细胞的极化依赖于完整的双侧 TDLN。RNA 测序数据表明，免疫细胞的浸润和抗肿瘤作用受损部分归因于肿瘤微环境中成分分泌的改变。
结论
TDLN 通过促进 CD8 T 细胞的浸润和维持 M1/M2 巨噬细胞比例在 iRT 中发挥关键作用。
Zotero 插件