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Immunological markers predict the prognosis of patients with squamous non-small cell lung cancer

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Abstract

Lung cancer has become the leading cause of cancer-related death worldwide. However, treatment failures still represent enormous challenges, and it is doubtful whether standard treatment modalities could continuously achieve substantial improvements. As one of the novel therapy strategies, PD-L1 has been shown the function of down-regulating T cell activation through receptor PD-1. Moreover, prognosis of cancer patients is based not only on tumor-related factors but also on host-related factors, particularly systemic inflammatory response. Significantly, squamous non-small cell lung cancer (NSCLC) revealed to be divergent clinical and molecular phenotypes compared with non-squamous NSCLC. Monocyte ratio, neutrophils to lymphocytes ratio, PD-L1 immunostaining score and PD-1-positive stained tumor-infiltrating lymphocyte counts were assessed by Fisher’s linear discriminant analysis to discriminate whether overall survival (OS) would exceeding 5 years. Finally, a prediction model was established for OS based on these immunological markers. Furthermore, this prediction model was validated in a second set of squamous NSCLC patients. The model offers a novel tool for survival prediction and could have important clinical implications for patients with squamous NSCLC, thus providing a framework for future individualized therapy.

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References

  1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29. doi:10.3322/caac.21208.

    Article  PubMed  Google Scholar 

  2. Devesa SS, Bray F, Vizcaino AP, Parkin DM. International lung cancer trends by histologic type: male:female differences diminishing and adenocarcinoma rates rising. Int J Cancer. 2005;117(2):294–9. doi:10.1002/ijc.21183.

    Article  CAS  PubMed  Google Scholar 

  3. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584–94. doi:10.4065/83.5.584.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Yasumoto K, Hanagiri T, Takenoyama M. Lung cancer-associated tumor antigens and the present status of immunotherapy against non-small-cell lung cancer. Gen Thorac Cardiovasc Surg. 2009;57(9):449–57. doi:10.1007/s11748-008-0433-6.

    Article  PubMed  Google Scholar 

  5. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64. doi:10.1038/nrc3239.

    Article  CAS  PubMed  Google Scholar 

  6. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5(12):1365–9. doi:10.1038/70932.

    Article  CAS  PubMed  Google Scholar 

  7. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239–45. doi:10.1038/ni1443.

    Article  CAS  PubMed  Google Scholar 

  8. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54. doi:10.1056/NEJMoa1200690.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65. doi:10.1056/NEJMoa1200694.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Boland JM, Kwon ED, Harrington SM, Wampfler JA, Tang H, Yang P, et al. Tumor B7-H1 and B7-H3 expression in squamous cell carcinoma of the lung. Clin Lung Cancer. 2013;14(2):157–63. doi:10.1016/j.cllc.2012.05.006.

    Article  CAS  PubMed  Google Scholar 

  11. Chen YB, Mu CY, Huang JA. Clinical significance of programmed death-1 ligand-1 expression in patients with non-small cell lung cancer: a 5-year-follow-up study. Tumori. 2012;98(6):751–5. doi:10.1700/1217.13499.

    PubMed  Google Scholar 

  12. Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 2004;10(15):5094–100. doi:10.1158/1078-0432.CCR-04-0428.

    Article  CAS  PubMed  Google Scholar 

  13. Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol. 2011;28(3):682–8. doi:10.1007/s12032-010-9515-2.

    Article  CAS  PubMed  Google Scholar 

  14. McMillan DC. Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care. 2009;12(3):223–6. doi:10.1097/MCO.0b013e32832a7902.

    Article  PubMed  Google Scholar 

  15. Roxburgh CS, McMillan DC. Role of systemic inflammatory response in predicting survival in patients with primary operable cancer. Future Oncol. 2010;6(1):149–63. doi:10.2217/fon.09.136.

    Article  CAS  PubMed  Google Scholar 

  16. Satomi A, Murakami S, Ishida K, Mastuki M, Hashimoto T, Sonoda M. Significance of increased neutrophils in patients with advanced colorectal cancer. Acta Oncol. 1995;34(1):69–73.

    Article  CAS  PubMed  Google Scholar 

  17. Sarraf KM, Belcher E, Raevsky E, Nicholson AG, Goldstraw P, Lim E. Neutrophil/lymphocyte ratio and its association with survival after complete resection in non-small cell lung cancer. J Thorac Cardiovasc Surg. 2009;137(2):425–8. doi:10.1016/j.jtcvs.2008.05.046.

    Article  PubMed  Google Scholar 

  18. Gomez D, Farid S, Malik HZ, Young AL, Toogood GJ, Lodge JP, et al. Preoperative neutrophil-to-lymphocyte ratio as a prognostic predictor after curative resection for hepatocellular carcinoma. World J Surg. 2008;32(8):1757–62. doi:10.1007/s00268-008-9552-6.

    Article  CAS  PubMed  Google Scholar 

  19. Sasaki A, Iwashita Y, Shibata K, Matsumoto T, Ohta M, Kitano S. Prognostic value of preoperative peripheral blood monocyte count in patients with hepatocellular carcinoma. Surgery. 2006;139(6):755–64. doi:10.1016/j.surg.2005.10.009.

    Article  PubMed  Google Scholar 

  20. Lee YY, Choi CH, Sung CO, Do IG, Huh S, Song T, et al. Prognostic value of pre-treatment circulating monocyte count in patients with cervical cancer: comparison with SCC-Ag level. Gynecol Oncol. 2012;124(1):92–7. doi:10.1016/j.ygyno.2011.09.034.

    Article  PubMed  Google Scholar 

  21. Zielinski C, Knapp S, Mascaux C, Hirsch F. Rationale for targeting the immune system through checkpoint molecule blockade in the treatment of non-small-cell lung cancer. Ann Oncol. 2013;24(5):1170–9. doi:10.1093/annonc/mds647.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi:10.1016/j.cell.2011.02.013.

    Article  CAS  PubMed  Google Scholar 

  23. Waki K, Yamada T, Yoshiyama K, Terazaki Y, Sakamoto S, Matsueda S, et al. PD-1 expression on peripheral blood T-cell subsets correlates with prognosis in non-small cell lung cancer. Cancer Sci. 2014;105(10):1229–35. doi:10.1111/cas.12502.

    Article  CAS  PubMed  Google Scholar 

  24. Shang B, Zhang G, Pan Y, Zhou Q. Deciphering the key features of malignant tumor microenvironment for anti-cancer therapy. Cancer Microenviron. 2012;5(3):211–23. doi:10.1007/s12307-012-0108-9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Yamazaki K, Spruill G, Rhoderick J, Spielman J, Savaraj N, Podack ER. Small cell lung carcinomas express shared and private tumor antigens presented by HLA-A1 or HLA-A2. Cancer Res. 1999;59(18):4642–50.

    CAS  PubMed  Google Scholar 

  26. Redondo M, Concha A, Oldiviela R, Cueto A, Gonzalez A, Garrido F, et al. Expression of HLA class I and II antigens in bronchogenic carcinomas: its relationship to cellular DNA content and clinical-pathological parameters. Cancer Res. 1991;51(18):4948–54.

    CAS  PubMed  Google Scholar 

  27. Samuels V, Barrett JM, Bockman S, Pantazis CG, Allen MJ. Immunocytochemical study of transforming growth factor expression in benign and malignant gliomas. Am J Pathol. 1989;134(4):894–902.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Oizumi S, Yamazaki K, Nakashima M, Watanabe T, Hommura F, Ogura S, et al. RCAS1 expression: a potential prognostic marker for adenocarcinomas of the lung. Oncology-Basel. 2002;62(4):333–9. doi:10.1159/000065065.

    Article  CAS  Google Scholar 

  29. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Chen C, Qu QX, Huang JA, Zhu YB, Ge Y, Wang Q, et al. Expression of programmed-death receptor ligands 1 and 2 may contribute to the poor stimulatory potential of murine immature dendritic cells. Immunobiology. 2007;212(3):159–65. doi:10.1016/j.imbio.2007.01.004.

    Article  CAS  PubMed  Google Scholar 

  31. Velcheti V, Rimm DL, Schalper KA. Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1). J Thorac Oncol. 2013;8(6):803–5. doi:10.1097/JTO.0b013e318292be18.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800. doi:10.1038/nm730.

    CAS  PubMed  Google Scholar 

  33. Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 2003;63(19):6501–5.

    CAS  PubMed  Google Scholar 

  34. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA. 2002;99(19):12293–7. doi:10.1073/pnas.192461099.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med. 2003;9(5):562–7. doi:10.1038/nm863.

    Article  CAS  PubMed  Google Scholar 

  36. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–7. doi:10.1038/nature01322.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Nagtegaal ID, Marijnen CA, Kranenbarg EK, Mulder-Stapel A, Hermans J, van de Velde CJ, et al. Local and distant recurrences in rectal cancer patients are predicted by the nonspecific immune response; specific immune response has only a systemic effect–a histopathological and immunohistochemical study. BMC Cancer. 2001;1:7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Droin N, Hendra JB, Ducoroy P, Solary E. Human defensins as cancer biomarkers and antitumour molecules. J Proteomics. 2009;72(6):918–27. doi:10.1016/j.jprot.2009.01.002.

    Article  CAS  PubMed  Google Scholar 

  39. Wong CP, Bray TM, Ho E. Induction of proinflammatory response in prostate cancer epithelial cells by activated macrophages. Cancer Lett. 2009;276(1):38–46. doi:10.1016/j.canlet.2008.10.025.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Okumura H, Matsumoto M, et al. Tumor-associated macrophage (TAM) infiltration in gastric cancer. Anticancer Res. 2003;23(5A):4079–83.

    CAS  PubMed  Google Scholar 

  41. Sasaki A, Kai S, Endo Y, Iwaki K, Uchida H, Tominaga M, et al. Prognostic value of preoperative peripheral blood monocyte count in patients with colorectal liver metastasis after liver resection. J Gastrointest Surg. 2007;11(5):596–602. doi:10.1007/s11605-007-0140-0.

    Article  PubMed  Google Scholar 

  42. Graziosi L, Marino E, De Angelis V, Rebonato A, Cavazzoni E, Donini A. Prognostic value of preoperative neutrophils to lymphocytes ratio in patients resected for gastric cancer. Am J Surg. 2015;209(2):333–7. doi:10.1016/j.amjsurg.2014.06.014.

    Article  PubMed  Google Scholar 

  43. Subimerb C, Pinlaor S, Lulitanond V, Khuntikeo N, Okada S, McGrath MS, et al. Circulating CD14(+) CD16(+) monocyte levels predict tissue invasive character of cholangiocarcinoma. Clin Exp Immunol. 2010;161(3):471–9. doi:10.1111/j.1365-2249.2010.04200.x.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Shamamian P, Schwartz JD, Pocock BJ, Monea S, Whiting D, Marcus SG, et al. Activation of progelatinase A (MMP-2) by neutrophil elastase, cathepsin G, and proteinase-3: a role for inflammatory cells in tumor invasion and angiogenesis. J Cell Physiol. 2001;189(2):197–206. doi:10.1002/jcp.10014.

    Article  CAS  PubMed  Google Scholar 

  45. Cho H, Hur HW, Kim SW, Kim SH, Kim JH, Kim YT, et al. Pre-treatment neutrophil to lymphocyte ratio is elevated in epithelial ovarian cancer and predicts survival after treatment. Cancer Immunol Immunother. 2009;58(1):15–23. doi:10.1007/s00262-008-0516-3.

    Article  CAS  PubMed  Google Scholar 

  46. Yamanaka T, Matsumoto S, Teramukai S, Ishiwata R, Nagai Y, Fukushima M. The baseline ratio of neutrophils to lymphocytes is associated with patient prognosis in advanced gastric cancer. Oncology-Basel. 2007;73(3–4):215–20. doi:10.1159/000127412.

    Article  Google Scholar 

  47. Petrie HT, Klassen LW, Kay HD. Inhibition of human cytotoxic T lymphocyte activity in vitro by autologous peripheral blood granulocytes. J Immunol. 1985;134(1):230–4.

    CAS  PubMed  Google Scholar 

  48. Crozier JE, McKee RF, McArdle CS, Angerson WJ, Anderson JH, Horgan PG, et al. Preoperative but not postoperative systemic inflammatory response correlates with survival in colorectal cancer. Br J Surg. 2007;94(8):1028–32. doi:10.1002/bjs.5706.

    Article  CAS  PubMed  Google Scholar 

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    Authors and Affiliations

    1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651, Dongfeng Rd East, Guangzhou, 510060, People’s Republic of China

      Long Jiang, Zerui Zhao, Shanshan Jiang, Yongbin Lin, Han Yang, Zehua Xie, Yaobin Lin & Hao Long

    2. Lung Cancer Institute of Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China

      Long Jiang, Zerui Zhao, Yongbin Lin, Han Yang, Zehua Xie, Yaobin Lin & Hao Long

    3. Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China

      Long Jiang, Zerui Zhao, Yongbin Lin, Han Yang, Zehua Xie, Yaobin Lin & Hao Long

    4. University of California, San Francisco, San Francisco, CA, USA

      Long Jiang

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    1. Long Jiang
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    Correspondence to Hao Long.

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    Long Jiang, Zerui Zhao and Shanshan Jiang have contributed equally to this article.

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    Jiang, L., Zhao, Z., Jiang, S. et al. Immunological markers predict the prognosis of patients with squamous non-small cell lung cancer. Immunol Res 62, 316–324 (2015). https://doi.org/10.1007/s12026-015-8662-0

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