Abstract
Pulmonary sarcomatoid cancer (PSC) is a rare, aggressive subtype of non-small cell lung cancer, and measures of local and systemic immunity as biomarkers are incompletely known. We performed this study to characterize the leukocyte composition within the tumor, stroma, and peripheral blood in patients with PSC and correlated our findings with overall survival. Tissue from 30 patients diagnosed with PSC was evaluated by IHC for the presence of CD3+, CD14+, and CD19+ cells and PD-L1 expression. A lymphocyte-to-monocyte ratio (LMR) was calculated for the tumor microenvironment (TME) and peripheral blood. Survival analyses were performed based on IHC scores or groups defined by receiver operating characteristic curve cutoffs. CD3+ and CD14+ cells were found throughout the TME. CD19+ cells were almost exclusive to the stroma and correlated with superior overall survival (HR 0.40, 95% CI 0.21–0.72, p = 0.003). Most patients expressed PD-L1 on the tumor and/or the infiltrating immune cells, but neither the presence nor PD-L1 expression level impacted survival. A more prolific immune infiltration of the TME was associated with improved survival (HR 0.82, 95% CI 0.70–0.98, p = 0.029). PSC patients with a TME LMR ≥1.2 had a median survival of 1598 versus 488 days for a TME LMR <1.2 (p = 0.010). In the peripheral blood, an LMR ≥2.3 was associated with improved median survival (1579 vs. 332 days, p < 0.001). Our data demonstrate multiple measures of the local and systemic immunity are associated with patient survival in PSC.
References
Dellon AL, Potvin C, Chretien PB. Prognostic value of pre-treatment lymphocyte count and T cell levels in localized bronchogenic carcinoma. J Surg Oncol. 1979;12(3):253–61.
Wesselius LJ, et al. Lymphocyte subsets in lung cancer. Chest. 1987;91(5):725–9.
Teramukai S, et al. Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: an analysis of Japan Multinational Trial Organisation LC00-03. Eur J Cancer. 2009;45(11):1950–8.
Kumagai S, et al. Prognostic impact of preoperative monocyte counts in patients with resected lung adenocarcinoma. Lung Cancer. 2014;85(3):457–64.
Hu P, et al. Prognostic significance of systemic inflammation-based lymphocyte-monocyte ratio in patients with lung cancer: based on a large cohort study. PLoS ONE. 2014;9(10):e108062.
Johnson SK, et al. Immune cell infiltrates and prognosis in primary carcinoma of the lung. Lung Cancer. 2000;27(1):27–35.
Ruffini E, et al. Clinical significance of tumor-infiltrating lymphocytes in lung neoplasms. Ann Thoracic Surg. 2009;87(2):365–71 (discussion 371–2).
Goc J, et al. Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells. Can Res. 2014;74(3):705–15.
Wakabayashi O, et al. CD4+ T cells in cancer stroma, not CD8+ T cells in cancer cell nests, are associated with favorable prognosis in human non-small cell lung cancers. Cancer Sci. 2003;94(11):1003–9.
Hiraoka K, et al. Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer. 2006;94(2):275–80.
Al-Shibli KI, et al. Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res. 2008;14(16):5220–7.
Kawai O, et al. Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer. 2008;113(6):1387–95.
Pelletier MP, et al. Prognostic markers in resectable non-small cell lung cancer: a multivariate analysis. Can J Surg. 2001;44(3):180–8.
Germain C, et al. Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer. Am J Respir Crit Care Med. 2014;189(7):832–44.
Suzuki K, et al. Clinical impact of immune microenvironment in stage I lung adenocarcinoma: tumor interleukin-12 receptor beta2 (IL-12Rbeta2), IL-7R, and stromal FoxP3/CD3 ratio are independent predictors of recurrence. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(4):490–8.
Yendamuri S, et al. Outcomes of sarcomatoid carcinoma of the lung: a surveillance, epidemiology, and end results database analysis. Surgery. 2012;152(3):397–402.
Kim S, et al. Programmed death-1 ligand 1 and 2 are highly expressed in pleomorphic carcinomas of the lung: comparison of sarcomatous and carcinomatous areas. Eur J Cancer. 2015;51:2698–707.
Vieira T, et al. Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1) and strong immune-cell infiltration by TCD3 cells and macrophages. Lung Cancer. 2016;98:51–8.
Terra SBSP, et al. Immunohistochemical study of 36 cases of pulmonary sarcomatoid carcinoma—sensitivity of TTF-1 is superior to napsin. Hum Pathol. 2014;45(2):294–302.
Mansfield AS, et al. B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis. J Thoracic Oncol Off Publ Int Assoc Study Lung Cancer. 2014;9(7):1036–40.
Krikman TW. Statistics to use. 1996 [cited 2015 October 16]; Available from http://www.physics.csbsju.edu/stats/.
Topalian Suzanne L, Drake Charles G, Pardoll Drew M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450–61.
Velcheti V, Rimm DL, Schalper KA. Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1). J Thoracic Oncol. 2013;8(6):803–5.
Gounant V, et al. Nivolumab-induced organizing pneumonitis in a patient with lung sarcomatoid carcinoma. Lung Cancer. 2016;99:162–5.
Raveglia F, et al. Personal experience in surgical management of pulmonary pleomorphic carcinoma. Ann Thoracic Surg. 2004;78(5):1742–7.
Bae H-M, et al. Palliative chemotherapy for pulmonary pleomorphic carcinoma. Lung Cancer. 2007;58(1):112–5.
Hong J, et al. The role of palliative chemotherapy for advanced pulmonary pleomorphic carcinoma. Med Oncol. 2009;26(3):287–91.
Chaft JE, et al. Clinical outcomes with perioperative chemotherapy in sarcomatoid carcinomas of the lung. J Thoracic Oncol. 2012;7(9):1400–5.
Vieira T, et al. Efficacy of first-line chemotherapy in patients with advanced lung sarcomatoid carcinoma. J Thoracic Oncol. 2013;8(12):1574–7.
Nishijima TF, et al. Prognostic value of lymphocyte-to-monocyte ratio in patients with solid tumors: a systematic review and meta-analysis. Cancer Treat Rev. 2015;41(10):971–8.
Li ZM, et al. Blood lymphocyte-to-monocyte ratio identifies high-risk patients in diffuse large B-cell lymphoma treated with R-CHOP. PLoS ONE. 2012;7(7):e41658.
Koh YW, et al. The ratio of the absolute lymphocyte count to the absolute monocyte count is associated with prognosis in Hodgkin’s lymphoma: correlation with tumor-associated macrophages. Oncologist. 2012;17(6):871–80.
Porrata LF, et al. Peripheral blood absolute lymphocyte/monocyte ratio during rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone treatment cycles predicts clinical outcomes in diffuse large B-cell lymphoma. Leuk Lymphoma. 2014;55(12):2728–38.
Fujiwara Y, et al. Postoperative peripheral absolute blood lymphocyte-to-monocyte ratio predicts therapeutic outcome after pancreatic resection in patients with pancreatic adenocarcinoma. Anticancer Res. 2014;34(9):5163–8.
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This work was supported by an intramural grant from the Department of Laboratory Medicine and Pathology, Mayo Clinic.
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Schenk, E., Boland, J., Mansfield, A. et al. Local and systemic immunity predict survival in patients with pulmonary sarcomatoid carcinoma. Med Oncol 34, 140 (2017). https://doi.org/10.1007/s12032-017-1000-8
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DOI: https://doi.org/10.1007/s12032-017-1000-8