Dipeptidyl peptidase 4 inhibition sensitizes radiotherapy by promoting T cell infiltration

ABSTRACT

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.

KEYWORDS:

• Chemokines
• DPP4
• immunotherapy
• radiotherapy
• T cells

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2268257

Additional information

Funding

This study was conducted with the support by the Key R & D program of Hubei Province (Grant No. 2020BCA068), National Natural Science Foundation of China (Grant No. 82102931, 82073354, 82002896, and 82102201), and China Postdoctoral Science Foundation (Grant No. 2020M682435).