Radiotherapy enhances CXCR3highCD8+ T cell activation through inducing IFNγ-mediated CXCL10 and ICAM-1 expression in lung cancer cells

Radiotherapy (RT) not only damages tumors but also induces interferon (IFN) expression in tumors. IFNs mediate PD-L1 to exhaust CD8(+) T cells, but which also directly impact tumor cells and potentially activate anti-tumor immune surveillance. Little is known about the contradictory mechanism of IFNs in regulating CD8(+) T-mediated anti-tumor activity in lung cancer. This study found that RT induced IFNs and CXCL9/10 expression in the RT-treated lung cancer cells. Specifically, RT- and IFN gamma-pretreated A549 significantly activated CD8(+) T cells, resulting in significant inhibition of A549 colony formation. RNAseq and consequent qPCR results revealed that IFN gamma induced PD-L1, CXCL10, and ICAM-1, whereas PD-L1 knockdown activated CD8(+) T cells, but ICAM-1 knockdown diminished CD8(+) T cell activation. We further demonstrated that CXCR3 and CXCL10 decreased in the CD8(+) T cells and nonCD8(+) PBMCs, respectively, in the patients with lung cancer that expressed lower reactivation as co-cultured with A549 cells. In addition, inhibitors targeting CXCR3 and LFA-1 in CD8(+) T cells significantly diminished CD8(+) T cell activation and splenocytes-mediated anti-LL/2shPdl1. In conclusion, we validated that RT suppressed lung cancer and overexpress PD-L1, CXCL10, and ICAM-1, which exhibited different roles in regulating CD8(+) T cell activity. We propose that CXCR3(high)CD8(+) T cells stimulated by CXCL10 exhibit anti-tumor immunity, possibly by enhancing T cells-tumor cells adhesion through CXCL10/CXCR3-activated LFA-1-ICAM-1 interaction, but CXCR3(low)CD8(+) T cells with low CXCL10 in patients with lung cancer were exhausted by PD-L1 dominantly. Therefore, RT potentially activates CD8(+) T cells by inducing IFNs-mediated CXCL10 and ICAM-1 expression in tumors to enhance CD8(+) T-tumor adhesion and recognition. This study clarified the possible mechanisms of RT and IFNs in regulating CD8(+) T cell activation in lung cancer.