The importance of alterations in innate lymphoid cell subsets in patients with non-small cell lung cancer and their role in tumorigenesis

Year 2023, Volume: 6 Issue: 2, 251 - 257, 31.08.2023

Duygu Ilke Cıkman , Esin Çetin Aktaş , Metin Yusuf Gelmez , Fehim Esen , Ayşe Engin , Akif Turna , Gunnur Deniz

https://doi.org/10.36516/jocass.1321787

Abstract

Objective. Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related morbidity and mortality. Diverse functions of innate lymphoid cells (ILCs) and NK cell subsets are investigated thoroughly in cancer immunotherapy. ILC and recently described NK cell subsets in NSCLC patients’ blood samples and tumor draining lymph nodes were investigated.
Methods. The study included chemotherapy and/or radiotherapy-naive NSCLC patients with clinical stage T1-4N0-2M0 who underwent video-assisted mediastinal lymphadenectomy and 14 healthy controls. Mononuclear cells were isolated from peripheral blood of both groups and mediastinal lymph nodes of NSCLC patients. NK cells and ILC subsets were analyzed by flow cytometry.
Results. Total NK cells are shown to be increased in peripheral blood of NSCLC patients compared to lymph nodes while the ratio of CD56dimCD16- exhausted NK cells is higher in lymph nodes than in blood samples of NSCLC patients. Compared to control group, peripheral blood ILC1 cells were lower in NSCLC patients, however ILC2 and ILC3 cells were significantly increased. However, mediastinal lymph nodes of NSCLC patients had decreased ratio of ILC2 and increased ratio of ILC3 cells than in peripheral blood of patients. NSCLC patients had significantly increased ratio of NKp44-ILC3 cells and decreased ratio of NKp44+ILC3 in lymph nodes.
Conclusion. Decreased ratio of ILC1 cells is an important indicator of impaired anti-tumoral response. Increased in the ratio of NKp44-ILC3 cells in NSCLC patients may potentially contribute to tumor progression. These findings highlight the distinct roles of ILCs, which play a pivotal role in the pathogenesis of lung cancer.

Keywords

NSCLC, NK cells, ILC1, ILC2, ILC3, Immunotherapy

Supporting Institution

Research Fund of Istanbul University

Project Number

Grant No: TOA-2017 20591

Küçük hücre dışı akciğer kanseri hastalarında doğal lenfoid hücre alt gruplarındaki değişiklikler ve tümör gelişimindeki olası rolleri

Abstract

Giriş: Küçük hücre dışı akciğer kanseri (KHDAK) tüm dünyada ciddi morbidite ve mortaliteye neden olmaktadır. Özellikle son yıllarda önemi daha iyi anlaşılan ILC (doğal lenfoid hücreler) alt gruplarındaki değişikliklerin tümör gelişiminde önemli rol oynayabileceği öne sürülmüştür. Bu çalışmada KHDAK hastalarında periferik kan ve tümörü drene eden mediastinal lenf nodlarındaki ILC alt grupları incelenmiştir.
Gereç ve Yöntemler: Çalışmamıza video yardımlı mediastinal lenfadenektomi uygulanan T1-4N0-2M0 evreli ve daha önce sistemik kemoterapi/radyoterapi almamış 13 KHDAK hastası ve 14 sağlıklı kontrol incelenmiştir. Periferik kan ve mediastinal lenf nodundan izole edilen lenfositlerde NK hücre ile ILC alt grupları akan hücre ölçer ile analiz edilmiştir.
Sonuç: KHDAK olguların kan örneklerinde total NK hücre oranı tümör drene eden lenf noduna kıyasla artmıştır. CD56dimCD16- tükenmiş NK hücrelerin oranı ise lenf nodu örneklerinde KHDAK hastaların kan örneklerine kıyasla daha yüksek saptanmıştır. KHDAK olguların kanında ILC1 oranı kontrol grubuna kıyasla daha düşük, ILC2 ve ILC3 alt gruplarının oranı ise daha yüksek bulunmuştur. Buna karşın KHDAK olguların mediastinal lenf nodunda aynı hastaların kan örneklerine göre ILC2 oranı düşük, ILC3 oranı ise yüksektir. KHDAK hastaların lenf nodunda NKp44-ILC3 oranı artmışken, NKp44+ILC3 oranı azalmıştır.
Tartışma: KHDAK hastalarında ILC1 hücre oranındaki azalma bozulmuş anti-tümöral immünitenin önemli bir göstergesidir. Tümör büyümesinde rol oynadığı düşünülen IL-17’yi salgılayan NKp44-ILC-3 hücre grubunun bu hastalarda artmış olması, bu hücrelerin tümör gelişiminde rolü olabileceğini düşündürmektedir. Bu bulgular ILC hücre ailesinin akciğer kanseri patogenezinde önemli rollere sahip olduğunun altını çizmektedir.

Keywords

KHDAK, NK hücre, ILC1, ILC2, ILC3, immünoterapi

Project Number

Grant No: TOA-2017 20591

References

• 1.Kaur J, Elms J, Munn AL, et al. Immunotherapy for non-small cell lung cancer (NSCLC), as a stand-alone and in combination therapy. Critical Re-views in Oncology/Hematology. 2021, 164: 103417. https://doi.org/10.1016/j.critrevonc.2021.103417
• 2.Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA: a cancer journal for clinicians. 2023; 73.1: 17-48. https://doi.org/10.3322/caac.21763
• 3.Alduais Y, Zhang H, Fan F. et al. Non-small cell lung cancer (NSCLC): a review of risk factors, diagnosis, and treatment. Medicine, 2023; 8: e32899-e32899. https://doi.org/10.1097/MD.0000000000032899
• 4.Albain KS, Swann RS, Rusch VR, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. The Lancet. 2009; 374: 379-86. https://doi.org/10.1016/S0140-6736(09)60737-6
• 5.Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradio-therapy in stage III non-small-cell lung cancer. New England Journal of Medicine. 2017; 377: 1919-29. https://doi.org/10.1056/NEJMoa1709937
• 6.Wu Y, Yuan M, Wang C, et al. T lymphocyte cell: A pivotal player in lung cancer [published correction appears in Front Immunol. 2023; 14: 1166352. https://doi.org/10.3389/fimmu.2023.1102778
• 7.Vivier E, Artis D, Colonna M, et al. Innate lymphoid cells: 10 years on. Cell. 2018; 174: 1054-66. https://doi.org/10.1016/j.cell.2018.07.017
• 8.Gasteiger G, Fan X, Dikiy S, et al. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science. 2015; 350: 981-5. https://doi.org/10.1126/science.aac9593
• 9.Crinier A, Narni-Mancinelli E, Ugolini S, et al. SnapShot: Natural Kill¬er Cells. Cell. 2020; 180(6): 1280.e1. https://doi.org/10.1016/j.cell.2020.02.029
• 10.Guillerey C, Huntington ND, Smyth MJ. Targeting natural killer cells in cancer immunotherapy. Nat Immunol. 2016; 17(9): 1025-36. https://doi.org/10.1038/ni.3518
• 11.Zaiss DMW, Gause WC, Osborne LC, et al. Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity. 2015; 42(2): 216-26. https://doi.org/10.1016/j.immuni.2015.01.020
• 12.Bie Q, Zhang P, Su Z, et al. Polarization of ILC2s in peripheral blood might contribute to immunosuppressive microenvironment in patients with gastric cancer. J Immunol Res. 2014;923135. https://doi.org/10.1155/2014/923135
• 13.Carrega P, Loiacono F, Di Carlo E, et al. NCR(+)ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures. Nat Commun. 2015; 6: 8280. https://doi.org/10.1038/ncomms9280
• 14.Yin G, Zhao C, Pei W. Crosstalk between macrophages and innate lymphoid cells (ILCs) in diseases. Int Immunopharmacol. 2022; 110: 108937. https://doi.org/10.1016/j.intimp.2022.108937
• 15.Bald T, Wagner M, Gao Y, et al. Hide and seek: Plasticity of innate lym-phoid cells in cancer. Semin Immunol. 2019; 41: 101273. https://doi.org/10.1016/j.smim.2019.04.001
• 16.Engin A, Turna A, Esen F, et al. Mediastinal lymph node removal ame-liorates cytotoxic T-lymphocyte functions in patients with non-small cell lung cancer. Tumori. 2023; 109(1): 97-104. https://doi.org/10.1177/03008916211064643
• 17.Amand M, Iserentant G, Poli A, et al. Human CD56dimCD16dim Cells As an Individualized Natural Killer Cell Subset. Front Immunol. 2017; 8: 699. https://doi.org/10.3389/fimmu.2017.00699
• 18.Ahmed H, Mahmud AR, Faijanur-Rob-Siddiquee M, et al. Role of T cells in cancer immunotherapy: Opportunities and challenges. Cancer Pathogene¬sis and Therapy. 2023;1.02: 116-26. https://doi.org/10.1016/j.cpt.2022.12.002
• 19.Munari E, Quatrini L, Ciancaglini C, et al. Immunotherapy targeting in-hibitory checkpoints: The role of NK and other innate lymphoid cells. Semin Immunol. 2022; 101660: 61-4. https://doi.org/10.1016/j.smim.2022.101660
• 20.Moretta A, Locatelli F, Moretta L. Human NK cells: from HLA class I-specific killer Ig-like receptors to the therapy of acute leukemias. Immunol Rev. 2008; 224: 58-69. https://doi.org/10.1111/j.1600-065X.2008.00651.x
• 21.Villegas FR, Coca S, Villarrubia VG, et al. Prognostic significance of tu-mor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. Lung Cancer. 2002; 35(1): 23-8. https://doi.org/10.1016/S0169-5002(01)00292-6
• 22.Coca S, Perez-Piqueras J, Martinez D, et al. The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer. 1997; 79(12): 2320-8. https://doi.org/10.1002/(SICI)1097-0142(19970615)79:12<2320::AID-CNCR5>3.0.CO;2-P
• 23.Soo RA, Chen Z, Yan Teng RS, et al. Prognostic significance of immune cells in non-small cell lung cancer: meta-analysis. Oncotarget. 2018; 9(37): 24801-20. https://doi.org/10.18632/oncotarget.24835
• 24.Malmberg KJ, Carlsten M, Björklund A, et al. Natural killer cell-mediated immunosurveillance of human cancer. Semin Immunol. 2017; 31: 20-9. https://doi.org/10.1016/j.smim.2017.08.002
• 25.Ducimetière L, Lucchiari G, Litscher G, et al. Conventional NK cells and tissue-resident ILC1s join forces to control liver metastasis. Proc Natl Acad Sci U S A. 2021; 118(27) :e2026271118. https://doi.org/10.1073/pnas.2026271118
• 26.Verma R, Er JZ, Pu RW, et al. Eomes Expression Defines Group 1 Innate Lymphoid Cells During Metastasis in Human and Mouse. Front Immunol. 2020; 11: 1190. https://doi.org/10.3389/fimmu.2020.01190
• 27.Saranchova I, Han J, Zaman R, et al. Type 2 Innate Lymphocytes Actu-ate Immunity Against Tumours and Limit Cancer Metastasis. Sci Rep. 2018; 8(1): 2924. https://doi.org/10.1038/s41598-018-20608-6
• 28.Chevalier MF, Trabanelli S, Racle J, et al. ILC2-modulated T cell-to-MDSC balance is associated with bladder cancer recurrence. J Clin Invest. 2017; 127(8): 2916-29. https://doi.org/10.1172/JCI89717
• 29.Shen C, Liu C, Zhang Z, et al. PD-1 Affects the Immunosuppressive Function of Group 2 Innate Lymphoid Cells in Human Non-Small Cell Lung Cancer. Front Immunol. 2021; 12: 680055. https://doi.org/10.3389/fimmu.2021.680055
• 30.Croxatto D, Micheletti A, Montaldo E, et al. Group 3 innate lymphoid cells regulate neutrophil migration and function in human decidua. Muco¬sal Immunol. 2016; 9(6):1372- 83. https://doi.org/10.1038/mi.2016.10
• 31.Liu Y, Song Y, Lin D, et al. NCR- group 3 innate lymphoid cells or-chestrate IL-23/IL-17 axis to promote hepatocellular carcinoma devel-opment. EBioMedicine. 2019; 41: 333-44. https://doi.org/10.1016/j.ebiom.2019.02.050
• 32.Wang K, Karin M. The IL-23 to IL-17 cascade inflammation-related cancers. Clin Exp Rheumatol. 2015; 33(4 Suppl 92): 87-90.