Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York.
Department of Surgery, University of Rochester Medical Center, Rochester, New York.
Int J Radiat Oncol Biol Phys. 2021 Sep 1;111(1):284-296. doi: 10.1016/j.ijrobp.2021.04.021. Epub 2021 Apr 30.
Dexamethasone is commonly given during radiation therapy (RT) to manage toxicities. Our study examines if dexamethasone coadministration with RT inhibits the RT-induced antitumor T cell response in mouse.
Intramuscularly implanted MC38 tumors were irradiated with 15 Gy after establishing for 7 days. Tumor bearing mice were administered dexamethasone using multiple schedules and doses. Peripheral lymphocyte reduction was monitored by complete blood count and intratumoral and tumor draining lymph node (tdLN) populations by flow cytometry. Effector phenotype and function of ex vivo stimulated tumor-infiltrating lymphocytes (TILs) and naïve splenocytes as well as in vivo TILs with or without dexamethasone were monitored by flow cytometry and ELISA.
Long course high dose, short course high dose, and short course human equivalent dose dexamethasone reduced peripheral lymphocytes yet did not inhibit survival after irradiation. Short course high dose administration decreased TIL and tdLN lymphocyte activation as well as tdLN mass but did not affect TIL frequencies or change tdLN cell population composition. Dexamethasone inhibited effector function of ex vivo stimulated naïve splenocytes and TILs, but magnitude of IFN-γ secretion was consistently higher in TILs regardless of dexamethasone dose. In vivo analysis of TILs after irradiation and HE dexamethasone treatment showed that TILs had a similar effector phenotype compared with vehicle controls.
Dexamethasone reduces blood and tdLN lymphocytes. Dexamethasone also suppresses TIL activation/effector function yet does not affect survival in irradiated MC38 tumor bearing mice, which depend on RT-induced immune responses for therapy efficacy. Additional study in human subjects is warranted.
地塞米松常用于放射治疗 (RT) 以控制毒性。我们的研究考察了地塞米松与 RT 联合应用是否会抑制 RT 诱导的小鼠抗肿瘤 T 细胞反应。
在建立 7 天后，用 15 Gy 照射肌肉内植入的 MC38 肿瘤。荷瘤小鼠采用多种方案和剂量给予地塞米松。通过全血细胞计数监测外周淋巴细胞减少，通过流式细胞术监测肿瘤内和肿瘤引流淋巴结 (tdLN) 群体。通过流式细胞术和 ELISA 监测体外刺激的肿瘤浸润淋巴细胞 (TIL) 和幼稚脾细胞以及有无地塞米松的体内 TIL 的效应表型和功能。
长疗程高剂量、短疗程高剂量和短疗程人等效剂量地塞米松减少外周淋巴细胞，但不抑制照射后的存活。短疗程高剂量给药降低了 TIL 和 tdLN 淋巴细胞的激活以及 tdLN 的质量，但不影响 TIL 的频率或改变 tdLN 细胞群体组成。地塞米松抑制了体外刺激的幼稚脾细胞和 TIL 的效应功能，但 IFN-γ 分泌的幅度在 TIL 中始终更高，与地塞米松剂量无关。照射后和 HE 地塞米松治疗的体内 TIL 分析表明，TIL 具有与载体对照相似的效应表型。
地塞米松减少血液和 tdLN 淋巴细胞。地塞米松还抑制 TIL 的激活/效应功能，但不影响照射的 MC38 荷瘤小鼠的存活，这取决于 RT 诱导的免疫反应的治疗效果。需要在人类受试者中进行进一步的研究。
