Department of Urology, University of California, Los Angeles, Los Angeles, California.
Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California.
Clin Cancer Res. 2021 Mar 1;27(5):1505-1515. doi: 10.1158/1078-0432.CCR-20-2293. Epub 2020 Nov 20.
The use of high-dose per fraction radiotherapy delivered as stereotactic body radiotherapy is a standard of care for prostate cancer. It is hypothesized that high-dose radiotherapy may enhance or suppress tumor-reactive immunity. The objective of this study was to assess both antitumor and immunosuppressive effects induced by high-dose radiotherapy in prostate cancer coclinical models, and ultimately, to test whether a combination of radiotherapy with targeted immunotherapy can enhance antitumor immunity.
We studied the effects of high-dose per fraction radiotherapy with and without anti-Gr-1 using syngeneic murine allograft prostate cancer models. The dynamic change of immune populations, including tumor-infiltrating lymphocytes (TIL), T regulatory cells (Treg), and myeloid-derived suppressive cells (MDSC), was evaluated using flow cytometry and IHC.
Coclinical prostate cancer models demonstrated that high-dose per fraction radiotherapy induced a rapid increase of tumor-infiltrating MDSCs and a subsequent rise of CD8 TILs and circulating CD8 T effector memory cells. These radiation-induced CD8 TILs were more functionally potent than those from nonirradiated controls. While systemic depletion of MDSCs by anti-Gr-1 effectively prevented MDSC tumor infiltration, it did not enhance radiotherapy-induced antitumor immunity due to a compensatory expansion of Treg-mediated immune suppression.
In allograft prostate cancer models, high-dose radiotherapy induced an early rise of MDSCs, followed by a transient increase of functionally active CD8 TILs. However, systemic depletion of MDSC did not augment the antitumor efficacy of high-dose radiotherapy due to a compensatory Treg response, indicating blocking both MDSCs and Tregs might be necessary to enhance radiotherapy-induced antitumor immunity.
大剂量分次放疗作为立体定向体部放疗是前列腺癌的标准治疗方法。据推测，高剂量放疗可能增强或抑制肿瘤反应性免疫。本研究的目的是评估大剂量放疗在前列腺癌临床前模型中引起的抗肿瘤和免疫抑制作用，并最终测试放疗与靶向免疫疗法相结合是否能增强抗肿瘤免疫。
我们使用同基因鼠同种异体前列腺癌模型研究了大剂量分次放疗联合或不联合抗-Gr-1 的作用。使用流式细胞术和免疫组化评估免疫细胞群体（包括肿瘤浸润淋巴细胞[TIL]、调节性 T 细胞[Treg]和髓系来源抑制细胞[MDSC]）的动态变化。
临床前前列腺癌模型表明，大剂量分次放疗迅速增加肿瘤浸润性 MDSC，并随后增加 CD8 TIL 和循环 CD8 T 效应记忆细胞。这些放疗诱导的 CD8 TIL 比非照射对照组的功能更强大。虽然抗-Gr-1 全身性耗尽 MDSC 可有效防止 MDSC 肿瘤浸润，但由于 Treg 介导的免疫抑制的代偿性扩张，它并没有增强放疗诱导的抗肿瘤免疫。
在同种异体前列腺癌模型中，大剂量放疗诱导 MDSC 的早期升高，随后功能性活性 CD8 TIL 短暂增加。然而，由于 Treg 反应的代偿性增加，MDSC 的全身性耗尽并未增强大剂量放疗的抗肿瘤疗效，表明阻断 MDSC 和 Treg 可能是增强放疗诱导抗肿瘤免疫所必需的。
