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

[Author] Galam Leem1, Minwoo Jeon2, Kun Woo Kim3, Seongju Jeong2, Seong Jin Choi2, Yong Joon Lee2, Eui-Soon Kim2, Jae-Ik Lee3, Seung Yeon Ha4, Su-Hyung Park2, Hyo Sup Shim5, Jin Gu Lee6, Shin Myung Kang7, Eui-Cheol Shin2

Correspondence to Professor Eui-Cheol Shin, Korea Advanced Institute of Science and Technology Biomedical Research Center, Daejeon 34141, Korea (the Republic of); ecshin@kaist.ac.kr; Dr Jin Gu Lee, Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea (the Republic of); csjglee@yuhs.ac; Dr Shin Myung Kang, Division of Pulmonology and Allergy, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea (the Republic of); shinm.kang@gmail.com

[Journal] 
Thorax, Aug 2022, Volume 77, Issue 8

[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)-γ (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)-γ after IL-15 treatment, and that IL-15 treatment in MCMV-infected mice upregulated tumour necrosis factor-α and IFN-γ responsive genes in tumour microenvironment.

Conclusion Thus, the study demonstrates that bystander CD8⁺ TILs can be repurposed by IL-15 for tumour immunotherapy.