Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Clin Cancer Res. 2018 Oct 15;24(20):5058-5071. doi: 10.1158/1078-0432.CCR-17-3427. Epub 2018 Jun 13.
In the proper context, radiotherapy can promote antitumor immunity. It is unknown if elective nodal irradiation (ENI), a strategy that irradiates tumor-associated draining lymph nodes (DLN), affects adaptive immune responses and combinatorial efficacy of radiotherapy with immune checkpoint blockade (ICB). We developed a preclinical model to compare stereotactic radiotherapy (Tumor RT) with or without ENI to examine immunologic differences between radiotherapy techniques that spare or irradiate the DLN. Tumor RT was associated with upregulation of an intratumoral T-cell chemoattractant chemokine signature (CXCR3, CCR5-related) that resulted in robust infiltration of antigen-specific CD8 effector T cells as well as FoxP3 regulatory T cells (Tregs). The addition of ENI attenuated chemokine expression, restrained immune infiltration, and adversely affected survival when combined with ICB, especially with anti-CLTA4 therapy. The combination of stereotactic radiotherapy and ICB led to long-term survival in a subset of mice and was associated with favorable CD8 effector-to-Treg ratios and increased intratumoral density of antigen-specific CD8 T cells. Although radiotherapy technique (Tumor RT vs. ENI) affected initial tumor control and survival, the ability to reject tumor upon rechallenge was partially dependent upon the mechanism of action of ICB; as radiotherapy/anti-CTLA4 was superior to radiotherapy/anti-PD-1. Our results highlight that irradiation of the DLN restrains adaptive immune responses through altered chemokine expression and CD8 T-cell trafficking. These data have implications for combining radiotherapy and ICB, long-term survival, and induction of immunologic memory. Clinically, the immunomodulatory effect of the radiotherapy strategy should be considered when combining stereotactic radiotherapy with immunotherapy. .
在适当的情况下，放射治疗可以促进抗肿瘤免疫。目前尚不清楚选择性淋巴结照射（ENI），即照射肿瘤相关引流淋巴结（DLN）的策略，是否会影响适应性免疫反应以及放射治疗联合免疫检查点阻断（ICB）的组合疗效。我们开发了一种临床前模型，比较了立体定向放疗（Tumor RT）加或不加 ENI，以检查保留或照射 DLN 的放疗技术之间的免疫学差异。Tumor RT 与肿瘤内 T 细胞趋化因子特征（CXCR3、CCR5 相关）的上调相关，导致抗原特异性 CD8 效应 T 细胞以及 FoxP3 调节性 T 细胞（Tregs）的大量浸润。加入 ENI 会减弱趋化因子表达，抑制免疫浸润，并在与 ICB 联合使用时，特别是与抗 CLTA4 治疗联合使用时，会产生不利影响。立体定向放疗和 ICB 的联合使用导致一部分小鼠的长期存活，并与有利的 CD8 效应细胞与 Treg 细胞的比例以及肿瘤内抗原特异性 CD8 T 细胞的密度增加相关。尽管放疗技术（Tumor RT 与 ENI）影响初始肿瘤控制和存活，但在重新挑战时抵抗肿瘤的能力部分取决于 ICB 的作用机制；放疗/抗 CTLA4 优于放疗/抗 PD-1。我们的结果强调，通过改变趋化因子表达和 CD8 T 细胞迁移，DLN 的照射会抑制适应性免疫反应。这些数据对于将放射治疗和 ICB 联合使用、长期存活和诱导免疫记忆具有重要意义。在临床上，当将立体定向放射治疗与免疫疗法结合使用时，应考虑放射治疗策略的免疫调节作用。
