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Lung cancer
Original research
Tumour-infiltrating bystander CD8+ T cells activated by IL-15 contribute to tumour control in non-small cell lung cancer
  1. Galam Leem1,
  2. Minwoo Jeon2,
  3. Kun Woo Kim3,
  4. Seongju Jeong2,
  5. Seong Jin Choi2,
  6. Yong Joon Lee2,
  7. Eui-Soon Kim2,
  8. Jae-Ik Lee3,
  9. Seung Yeon Ha4,
  10. Su-Hyung Park2,
  11. Hyo Sup Shim5,
  12. Jin Gu Lee6,
  13. Shin Myung Kang7,
  14. Eui-Cheol Shin2
  1. 1 Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
  2. 2 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (the Republic of)
  3. 3 Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Incheon, Korea (the Republic of)
  4. 4 Department of Pathology, Gachon University Gil Medical Center, Incheon, Korea (the Republic of)
  5. 5 Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
  6. 6 Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
  7. 7 Division of Pulmonology and Allergy, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea (the Republic of)
  1. Correspondence to Professor Eui-Cheol Shin, Korea Advanced Institute of Science and Technology Biomedical Research Center, Daejeon 34141, Korea (the Republic of); ecshin{at}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{at}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{at}gmail.com

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.

  • non-small cell lung cancer
  • lung cancer

Data availability statement

RNA sequencing data are uploaded on Gene Expression Omnibus (GEO) database. GEO accession number is GSE185243. All other data that support the findings of this study are available from the corresponding author ECS upon reasonable request.

https://doi.org/10.1136/thoraxjnl-2021-217001

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    Data availability statement

    RNA sequencing data are uploaded on Gene Expression Omnibus (GEO) database. GEO accession number is GSE185243. All other data that support the findings of this study are available from the corresponding author ECS upon reasonable request.

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    Footnotes

    • GL, MJ and KWK contributed equally.

    • Contributors Conception and design: GL, KWK, SJ, YJL, S-HP, JGL, SMK and E-CS. Financial support: JGL, SMK and E-CS. Administrative support: GL, KWK, SJ, MJ, SJC, E-SK, J-IL, SYH, JGL, SMK and E-CS. Provision of study materials or patients: GL, KWK, SJ, MJ, SJC, E-SK, J-IL, SYH, JGL, SMK and E-CS. Collection and assembly of data: GL, MJ, KWK, SJ, MJ, SJC, E-SK and E-CS. Data analysis and interpretation: GL, MJ, SJ, SJC, JGL, SMK and E-CS. Manuscript writing: all authors. Final approval of manuscript: all authors. Guarantor: E-CS.

    • Funding This study was supported by National Research Foundation Grant NRF-2018M3A9D3079498 which are funded by the Ministry of Science and ICT.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.