放疗可以调节全身抗肿瘤免疫，而肿瘤微环境（TME）的免疫状态也影响放疗的疗效。我们发现，较高的 CD8 T 细胞浸润与接受放疗的肺腺癌和黑色素瘤患者的总生存期较长有关。 8-Gray 辐射增加了体外肿瘤细胞中趋化因子的转录水平。然而，这不足以在体内诱导显着的淋巴细胞浸润。据报道，二肽基肽酶 4 (DPP4) 可通过翻译后截短使趋化因子失活。单细胞测序显示，树突状细胞 (DC) 在 TME 中的其他细胞中具有较高的 DPP4 表达，并且在辐射后 DPP4 表达上调。 DPP4抑制剂联合放疗可以促进TME中趋化因子的表达和T细胞浸润，增强放疗的抗肿瘤效果。此外，该疗法进一步增强了抗PD-1的治疗效果。在这项研究中，我们论证了放疗未能诱导足够的T细胞浸润的根本机制，并提出了促进T细胞浸润和提高放疗敏感性的有效策略。这些发现证明了 DPP4 抑制作为增强放疗疗效以及放疗与免疫治疗相结合的补充方法的转化价值。© 2023 作者。经泰勒许可出版

Radiotherapy could regulate systemic antitumor immunity, while the immune state in the tumor microenvironment (TME) also affects the efficacy of radiotherapy. We have found that higher CD8+ T cell infiltration is associated with longer overall survival of lung adenocarcinoma and melanoma patients receiving radiotherapy. 8-Gray radiation increased the transcriptional levels of chemokines in tumor cells in vitro. However, it was not sufficient to induce significant lymphocyte infiltration in vivo. Dipeptidyl peptidase 4 (DPP4) has been reported to inactivate chemokines via post-translational truncation. Single-cell sequencing revealed that dendritic cells (DCs) had a higher DPP4 expression among other cells in the TME and upregulated DPP4 expression after radiation. Combining a DPP4 inhibitor with radiotherapy could promote chemokines expression and T cell infiltration in the TME, enhancing the antitumor effect of radiotherapy. Moreover, this therapy further enhanced the therapeutic efficacy of anti-PD-1. In this study, we demonstrated the underlying mechanism of why radiotherapy failed to induce sufficient T cell infiltration and proposed an effective strategy to promote T cell infiltration and sensitize radiotherapy. These findings demonstrate the translational value of DPP4 inhibition as a complementary approach to enhance the efficacy of radiotherapy and the combination of radiotherapy with immunotherapy.© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.