Polymorphonuclear-MDSCs Facilitate Tumor Regrowth After Radiation by Suppressing CD8⁺ T Cells

Radiation therapy (RT) is widely used in the treatment of cancer. Unfortunately, RT alone is insufficient to control the disease in most cases, as regrowth after irradiation still occur. Thus, it would be meaningful to explore the underlying mechanism of tumor regrowth after irradiation. Myeloid-derived suppressor cells (MDSCs) contribute to the immunosuppressive tumor microenvironment and hinder the therapeutic efficacy of RT. However, it is unclear whether MDSCs-mediated immune suppression contributes to local relapse after irradiation. In this article, we tried to figure out how MDSCs sabotage the therapeutic effect of RT, and tried to determine the potential synergistic effect of combination between targeting MDSCs and RT.

A syngeneic murine model of Lewis lung cancer was used. The abundance of tumor infiltrating MDSCs and tumor growth after irradiation was assessed. The percentage and functional state of CD8⁺ T cells were measured by flow cytometry, with or without polymorphonuclear (PMN)-MDSCs depletion. Arginase 1 (ARG1) expression and activity of MDSCs were examined by hematoxylin and eosin staining and flow cytometry. ARG1 inhibitor and phosphodiesterase 5 inhibitor sildenafil were administered after RT to figure out the underlying mechanism of MDSCs-mediated immunosuppression.

We demonstrated that irradiation recruited MDSCs, especially the polymorphonuclear subset, into the tumor microenvironment. PMN-MDSCs inhibited the CD8⁺ T cell response by elevating ARG1 expression. Selective depletion of PMN-MDSCs or inhibition on ARG1 promoted the infiltration and activation of intratumoral CD8⁺ T cells, and delayed tumor regrowth after irradiation. We showed that sildenafil reduced the accumulation and ARG1 expression of PMN-MDSCs after irradiation, thus abrogating the MDSCs-mediated immunosuppression.

Our results have suggested that PMN-MDSCs participate in the irradiation-induced immune suppression through ARG1 activation. We have also found that sildenafil has the potential to facilitate antitumor immunity, which provides a new alternative to delay tumor recurrence after RT.