Radiotherapy enhances CXCR3highCD8+ T cell activation through inducing IFNγ-mediated CXCL10 and ICAM-1 expression in lung cancer cells
Chih‐Liang Wang, Ai‐Sheng Ho, Chun‐Chao Chang, Zong‐Lin Sie, Cheng‐Liang Peng, Jungshan Chang, Chun‐Chia Cheng
Abstract
Abstract 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 IFNγ-pretreated A549 significantly activated CD8 + T cells, resulting in significant inhibition of A549 colony formation. RNAseq and consequent qPCR results revealed that IFNγ 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.