Tumour-infiltrating bystander CD8(+) T cells activated by IL-15 contribute to tumour control in non-small cell lung cancer

Abstract

Background Tumour-unrelated, virus-specific bystander CD8(+) T cells were recently shown to be abundant among tumour-infiltrating lymphocytes (TILs). However, their roles in tumour immunity have not been elucidated yet. Methods We studied the characteristics of bystander CD8(+) TILs from non-small cell lung cancer (NSCLC) tissues (N=66) and their activation by interleukin (IL)-15 to repurpose them for tumour immunotherapy. Results We show that bystander CD8(+) TILs specific to various viruses are present in human NSCLC tissues. We stimulated CD8(+) TILs ex vivo using IL-15 without cognate antigens and found that IL-15 treatment upregulated NKG2D expression on CD8(+) TILs, resulting in NKG2D-dependent production of interferon (IFN)-gamma (p=0.0006). Finally, we tested whether IL-15 treatment can control tumour growth in a murine NSCLC model with or without a history of murine cytomegalovirus (MCMV) infection. IL-15 treatment reduced the number of tumour nodules in the lung only in mice with MCMV infection (p=0.0037). We confirmed that MCMV-specific bystander CD8(+) TILs produced interferon (IFN)-gamma after IL-15 treatment, and that IL-15 treatment in MCMV-infected mice upregulated tumour necrosis factor-alpha and IFN-gamma responsive genes in tumour microenvironment. Conclusion Thus, the study demonstrates that bystander CD8(+) TILs can be repurposed by IL-15 for tumour immunotherapy.