Catalpol Reactivates IL-7R-STAT5 Signaling and Reverses Radiation-Induced T Helper 1 Cells Deficiency to Limit Melanoma Metastasis to Lung.

BACKGROUND

Radiation-induced quantitative deficiency of T helper 1 (Th1) cells accelerates lung tumor development. Here, we evaluated IL-7R-STAT5 signaling in Th1 recovery after irradiation and examined how catalpol contributes to Th1 reconstitution by targeting this signaling axis in mice.

METHODS

The recovery characteristics of irradiated Th1 cells, compared with other IFN-γ-producing (IFN-γ+) cells, were analyzed in local radiotherapy (LRT) mice challenged with lung melanoma and single low-dose total body irradiation (SLTBI) mice without tumor. IL-7R-STAT5 signaling of Th1 from LRT mice, treated with or without catalpol, was evaluated using flow cytometry and RT-qPCR. The role of IL-7-IL-7R-STAT5 signaling in irradiated Th1 cells was further confirmed in irradiated EL4 cells following administration of IL-7 or catalpol.

RESULTS

Th1 subsets showed delayed recovery in both LRT and SLTBI mice compared with other IFN-γ+ cells, and irradiated Th1 cells exhibited decreased activation of IL-7R-STAT5 signaling. Quantitative reduction of Th1 cells increased lung metastasis of B16 melanoma in irradiated mice. Irradiated EL4 cells also displayed decreased IL-7R-STAT5 signaling and reduced IFN-γ production in vitro. Treatment with catalpol could restore IL-7R-STAT5 signaling and promote Th1 recovery following irradiation both in vivo and in vitro. Catalpol-mediated restoration of IL-7R-STAT5 signaling in Th1 provided superior protection against B16 melanoma metastasis to the lung.

CONCLUSIONS

IL-7R-STAT5 signaling is required for Th1 recovery after irradiation. Catalpol effectively promotes Th1 cell reconstitution and decreases B16 melanoma metastasis to the lung by enhancing IL-7R-STAT5 signaling. These findings provide new strategies for improving radiotherapy and immunotherapy outcomes in cancer.