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Peripheral NK cells identified as the predictor of response in extensive-stage small cell lung cancer patients treated with first-line immunotherapy plus chemotherapy

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Abstract

Purpose

Although immunotherapy improves outcomes in extensive-stage small-cell lung cancer (ES-SCLC), the search for biomarkers predicting treatment success is crucial. Natural killer (NK) cells are potential indicators in various cancers, however, their precise role in ES-SCLC prognosis remains unclear.

Methods

In this retrospective study, 33 patients with ES-SCLC treated with first-line immuno-chemotherapy were enrolled. The peripheral NK cell percentage and its longitudinal dynamics were analyzed using flow cytometry. Progression-free survival (PFS) and overall survival (OS) were calculated as hazard ratio (HR) and compared statistically.

Results

The median PFS was better in the group with normal baseline NK cell levels than the low group (7.0 vs. 4.6 months; HR = 0.17; 95% CI 0.07–0.41; P < 0.0001), but there was no association with OS (14.9 vs. 10.3 months; HR = 0.55; 95% CI 0.23–1.31; P = 0.171). Furthermore, the NK cell% for 95.0% of patients increased after immunochemotherapy in the clinical response group (P = 0.0047), which led to a better median PFS (6.3 vs. 2.1 months; HR = 0.23; 95% CI 0.05–0.98; P < 0.0001) and OS (14.9 vs. 5.9 months; HR = 0.20; 95% CI 0.04–1.02; P < 0.0001). Similar trends were observed with NK cell% changes up to disease progression, improving PFS (6.5 vs. 4.3; HR = 0.41; 95% CI 0.12–0.92; P = 0.0049) and OS (17.4 vs. 9.7; HR = 0.42; 95% CI 0.17–1.02; P < 0.0001).

Conclusion

In patients with ES-SCLC, the percentage and changes in peripheral NK cells can predict the response to combined immunotherapy and chemotherapy.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Megyesfalvi Z, Gay CM, Popper H, Pirker R, Ostoros G, Heeke S, et al. Clinical insights into small cell lung cancer: tumor heterogeneity, diagnosis, therapy, and future directions. CA Cancer J Clin. 2023;73:620–52.

    Article  PubMed  Google Scholar 

  2. Rudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. Nat Rev Dis Primers. 2021;7:3.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Farago AF, Keane FK. Current standards for clinical management of small cell lung cancer. Transl Lung Cancer Res. 2018;7:69–79.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379:2220–9.

    Article  CAS  PubMed  Google Scholar 

  5. Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394:1929–39.

    Article  CAS  PubMed  Google Scholar 

  6. Wang J, Zhou C, Yao W, Wang Q, Min X, Chenet G, et al. Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022;23:739–47.

    Article  CAS  PubMed  Google Scholar 

  7. Cheng Y, Han L, Wu L, Chen J, Sun HBS, G W, et al. Effect of first-line serplulimab vs placebo added to chemotherapy on survival in patients with extensive-stage small cell lung cancer the ASTRUM-005 randomized clinical trial. JAMA. 2022;328:1223–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Remon J, Aldea M, Besse B, Planchard D, Reck M, Giaccone G, et al. Small cell lung cancer: a slightly less orphan disease after immunotherapy. Ann Oncol. 2021;32:698–709.

    Article  CAS  PubMed  Google Scholar 

  9. Doroshow DB, Bhalla S, Beasley MB, Sholl LM, Kerr KM, Gnjatic S, et al. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol. 2021;18:345–62.

    Article  CAS  PubMed  Google Scholar 

  10. Liu SV, Reck M, Mansfield AS, Mok T, Scherpereel A, Reinmuth N, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021;39:619–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Goldman JW, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021;22:51–65.

    Article  CAS  PubMed  Google Scholar 

  12. Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21:1353–65.

    Article  CAS  PubMed  Google Scholar 

  13. Hamilton G, Rath B. Immunotherapy for small cell lung cancer: mechanisms of resistance. Expert Opin Biol Ther. 2019;19:423–32.

    Article  CAS  PubMed  Google Scholar 

  14. Rudin CM, Balli D, Lai WV, Richards AL, Nguyen E, Egger JV, et al. Clinical benefit from immunotherapy in patients with SCLC is associated with tumor capacity for antigen presentation. J Thorac Oncol. 2023;18:1222–32.

    Article  CAS  PubMed  Google Scholar 

  15. Best SA, Hess JB, Souza-Fonseca-Guimaraes F, Cursons J, Kersbergen A, Donget X, et al. Harnessing natural killer immunity in metastatic SCLC. J Thorac Oncol. 2020;15:1507–21.

    Article  CAS  PubMed  Google Scholar 

  16. Shapiro, HM. Practical flow cytometry: shapiro/flow cytometry 4e. 2005.

  17. Bald T, Krummel MF, Smyth MJ, Barry KC. The NK cell-cancer cycle: advances and new challenges in NK cell-based immunotherapies. Nat Immunol. 2020;21:835–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Laskowski TJ, Biederstädt A, Rezvani K. Natural killer cells in antitumour adoptive cell immunotherapy. Nat Rev Cancer. 2022;22:557–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. **e MZ, Tang YP, Hu BL, Li KZ, Li JL, Liang XQ. Percentage of natural killer (NK) cells in peripheral blood is associated with prognosis in patients with gastric cancer: a retrospective study from a single center. Med Sci Monit Int J Clin Exp. 2021;27:e927464.

    CAS  Google Scholar 

  20. Tang YP, **e MZ, Li KZ, Li JL, Cai ZM, Hu BL. Prognostic value of peripheral blood natural killer cells in colorectal cancer. BMC Gastroenterol. 2020;20:31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhou J, Lin H-P, Xu X, Wang XH, Rong L, Zhang Y, et al. The predictive value of peripheral blood cells and lymphocyte subsets in oesophageal squamous cell cancer patients with neoadjuvant chemoradiotherapy. Front Immunol. 2022;13:1041126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tenuta M, Pandozzi C, Sciarra F, Campolo F, Gelibter AJ, Sirgiovanni G, et al. Circulating natural killer cells as prognostic value for non-small-cell lung cancer patients treated with immune checkpoint inhibitors: correlation with sarcopenia. Cancers (Basel). 2023;15:3592.

    Article  CAS  PubMed  Google Scholar 

  23. Ma W, Wei S, Long S, Tian EC, McLaughlin B, Jaimes M, et al. Dynamic evaluation of blood immune cells predictive of response to immune checkpoint inhibitors in NSCLC by multicolor spectrum flow cytometry. Front Immunol. 2023;14:1206631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pockley AG, Vaupel P, Multhoff G. NK cell-based therapeutics for lung cancer. Expert Opin Biol Ther. 2020;20:23–33.

    Article  CAS  PubMed  Google Scholar 

  25. Zhu M, Huang Y, Bender ME, Girard L, Kollipara R, Eglenen-Polat B, et al. Evasion of innate immunity contributes to small cell lung cancer progression and metastasis. Cancer Res. 2021;81:1813–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gay CM, Stewart CA, Park EM, Diao L, Groves SM, Heeke S, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021;39:346–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jeon EY, Choi DS, Choi S, Won JY, Jo Y, Kim HB, et al. Enhancing adoptive T-cell therapy with fucoidan-based IL-2 delivery microcapsules. Bioeng Transl Med. 2022;8: e10362.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Burr ML, Sparbier CE, Chan KL, Chan YC, Kersbergen A, Lam EYN, et al. An evolutionarily conserved function of polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer. Cancer Cell. 2019;36:385–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fousek K, Horn LA, Qin H, Dahut M, Iida M, Yacubovich D, et al. An interleukin-15 superagonist enables antitumor efficacy of natural killer cells against all molecular variants of SCLC. J Thorac Oncol. 2023;18:350–68.

    Article  CAS  PubMed  Google Scholar 

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Funding

This research was funded by the National Natural Science Foundation of China (Grant Number: 82103343) and the Tian** Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A).

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Authors and Affiliations

  1. Tian** Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tian**, 300060, China

    Yanan Cui, Yan** Chen & ** Chen & ** Chen & ** Chen & **ubao Ren

  2. Division of Thoracic Oncology, Jilin Cancer Hospital, Changchun, China

    Yanan Cui & Ying Cheng

  3. Translational Oncology Research Lab, Jilin Cancer Hospital, Changchun, China

    Peiyan Zhao

  4. Big Data Center of Clinical, Jilin Cancer Hospital, Changchun, China

    Shuang Li

Authors
  1. Yanan Cui
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  2. Yan** Chen
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  5. Ying Cheng
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  6. **ubao Ren
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Correspondence to Ying Cheng or **ubao Ren.

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The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethical Committee of Jilin Cancer Hospital, and individual consent for this retrospective analysis was waived.

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Cui, Y., Chen, Y., Zhao, P. et al. Peripheral NK cells identified as the predictor of response in extensive-stage small cell lung cancer patients treated with first-line immunotherapy plus chemotherapy. Clin Transl Oncol (2024). https://doi.org/10.1007/s12094-024-03479-4

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