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*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

6 Scopus citations

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 CXCR3highCD8+ 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 CXCR3lowCD8+ 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.

Original languageEnglish
Pages (from-to)1865-1880
Number of pages16
JournalCancer Immunology Immunotherapy
Volume72
Issue number6
DOIs
StatePublished - 06 2023

Bibliographical note

© 2023. The Author(s).

Keywords

  • CD8 T cells
  • CXCL10
  • CXCR3
  • ICAM-1
  • IFNγ
  • Lung cancer
  • PD-L1
  • Radiotherapy
  • STAT3
  • Intercellular Adhesion Molecule-1/metabolism
  • B7-H1 Antigen/metabolism
  • Humans
  • Lung Neoplasms/radiotherapy
  • Interferon-gamma/metabolism
  • CD8-Positive T-Lymphocytes
  • Receptors, CXCR3/genetics
  • Lymphocyte Function-Associated Antigen-1/metabolism
  • Chemokine CXCL10/metabolism

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