Advertisement
Original Research| Volume 55, P7-14, March 2016

Download started.

Ok

Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy

Published:January 06, 2016DOI:https://doi.org/10.1016/j.ejca.2015.11.020

      Highlights

      • There was a trend for poor survival in stage III non-small cell lung cancer who expressed programmed cell death-ligand 1 (PD-L1).
      • A combination of lack of PD-L1 expression and CD8+ tumour-infiltrating lymphocyte (TIL) density tended to predict favourable survival.
      • PD-L1 in combination with CD8+ TIL could be a useful predictive biomarker.

      Abstract

      Background

      Expression of programmed cell death-ligand 1 (PD-L1) is known to be a mechanism whereby cancer can escape immune surveillance, but little is known about factors predictive of efficacy in patients with locally advanced non-small cell lung cancer (NSCLC). We investigated the predictive relevance of PD-L1 expression and CD8+ tumour-infiltrating lymphocytes (TILs) density in patients with locally advanced NSCLC receiving concurrent chemoradiotherapy (CCRT).

      Methods

      We retrospectively reviewed 74 consecutive patients with stage III NSCLC who had received CCRT. PD-L1 expression and CD8+ TIL density were evaluated by immunohistochemical analysis.

      Results

      Univariate and multivariate analyses demonstrated that CD8+ TIL density was an independent and significant predictive factor for progression-free survival (PFS) and OS, whereas PD-L1 expression was not correlated with PFS and OS. Sub-analysis revealed that the PD-L1+/CD8 low group had the shortest PFS (8.6 months, p = 0.02) and OS (13.9 months, p = 0.11), and that the PD-L1-/CD8 high group had the longest prognosis (median PFS and OS were not reached) by Kaplan-Meier curves of the four sub-groups.

      Conclusions

      Among stage III NSCLC patients who received CCRT, there was a trend for poor survival in those who expressed PD-L1. Our analysis indicated that a combination of lack of PD-L1 expression and CD8+ TIL density was significantly associated with favourable survival in these patients. It is proposed that PD-L1 expression in combination with CD8+ TIL density could be a useful predictive biomarker in patients with stage III NSCLC.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Siegel R.
        • Naishadham D.
        • Jemal A.
        Cancer statistics.
        CA Cancer J Clin. 2012; 62: 10-29
        • Blackstock A.W.
        • Govindan R.
        Definitive chemoradiation for the treatment of locally advanced non small-cell lung cancer.
        J Clin Oncol. 2007; 25: 4146-4152
        • National Comprehensive Cancer Network
        NCCN clinical practice guidelines in oncology: non-small cell lung cancer.
        NCCN, Fort Washington, PA2014
        • Segawa Y.
        • Kiura K.
        • Takigawa N.
        • Kamei H.
        • Harita S.
        • Hiraki S.
        • et al.
        Phase III trial comparing docetaxel and cisplatin combination chemotherapy with mitomycin, vindesine, and cisplatin combination chemotherapy with concurrent thoracic radiotherapy in locally advanced non-small-cell lung cancer: OLCSG 0007.
        J Clin Oncol. 2010; 28: 3299-3306
        • Yamamoto N.
        • Nakagawa K.
        • Nishimura Y.
        • Tsujino K.
        • Satouchi M.
        • Kudo S.
        • et al.
        Phase III study comparing second- and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III non-small cell lung cancer: West Japan Thoracic Oncology Group WJTOG0105.
        J Clin Oncol. 2010; 28: 3739-3745
        • Horinouchi H.
        • Sekine I.
        • Sumi M.
        • Noda K.
        • Goto K.
        • Mori K.
        • et al.
        Long-term results of concurrent chemoradiotherapy using cisplatin and vinorelbine for stage III non-small-cell lung cancer.
        Cancer Sci. 2013; 104: 93-97
        • Pardoll D.M.
        The blockade of immune checkpoints in cancer immunotherapy.
        Nat Rev Cancer. 2012; 12: 252-264
        • Brahmer J.R.
        • Tykodi S.S.
        • Chow L.Q.M.
        • Hwu W.J.
        • Topalian S.L.
        • Hwu P.
        • et al.
        Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
        N Engl J Med. 2012; 366: 2455-2465
        • Rizvi N.A.
        • Mazières J.
        • Planchard D.
        • Stinchcombe T.E.
        • Dy G.K.
        • Antonia S.J.
        • et al.
        Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial.
        Lancet Oncol. 2015; 16: 257-265
        • Garon E.B.
        • Rizvi N.A.
        • Hui R.
        • Leighl N.
        • Balmanoukian A.S.
        • Eder J.P.
        • et al.
        Pembrolizumab for the treatment of non–small-cell lung cancer.
        N Engl J Med. 2015; 372: 2018-2028
        • Brahmer J.R.
        Harnessing the immune system for the treatment of non-small-cell lung cancer.
        J Clin Oncol. 2013; 31: 1021-1028
        • Hamid O.
        • Schmidt H.
        • Nissan A.
        • Ridolfi L.
        • Aamdal S.
        • Hansson J.
        • et al.
        A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma.
        J Transl Med. 2011; 9: 204
        • Sznol M.
        • Chen L.
        Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer.
        Clin Cancer Res. 2013; 19: 1021-1034
        • Herbst R.S.
        • Soria J.C.
        • Kowanetz M.
        • Fine G.D.
        • Hamid O.
        • Gordon M.S.
        • et al.
        Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.
        Nature. 2014; 515: 563-567
        • Brrahmer J.
        • Reckamp K.L.
        • Baas P.
        • Crinò L.
        • Eberhardt W.E.
        • Poddubskawa E.
        • et al.
        Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.
        N Engl Med. 2015; 373: 123-135
        • Schmidt L.H.
        • Kümmel A.
        • Görlich D.
        • Mohr M.
        • Bröckling S.
        • Mikesch J.H.
        • et al.
        PD-1 and PD-L1 expression in NSCLC indicate a favorable prognosis in defined subgroups.
        PLoS One. 2015; 10: e0136023
        • 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: 5094-5100
        • Boland J.M.
        • Kwon E.D.
        • Harrington S.M.
        • Wampfler J.A.
        • 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: 157-163
        • Mu C.-Y.
        • Huang J.-A.
        • Chen Y.
        • Chen C.
        • Zhang X.G.
        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: 682-688
        • Chen Y.B.
        • Mu C.Y.
        • Huang J.A.
        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: 751-755
        • Zhang Y.
        • Wang L.
        • Li Y.
        • Pan Y.
        • Wang R.
        • Hu H.
        • et al.
        Protein expression of programmed death 1 ligand 1 and ligand 2 independently predict poor prognosis in surgically resected lung adenocarcinoma.
        Onco Targets and Therapy. 2014; 7: 567-573
        • Velcheti V.
        • Schalper K.A.
        • Carvajai D.E.
        • Anagnostou V.K.
        • Syrigos K.N.
        • Sznol M.
        • et al.
        Programmed death ligand-1 expression in non-small cell lung cancer.
        Lab Invest. 2014; 94: 107-116
        • Brahmer J.R.
        • Drake C.G.
        • Wollner I.
        • Powderly J.D.
        • Picus J.
        • Sharfman W.H.
        • et al.
        Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.
        J Clin Oncol. 2010; 28: 3167-3175
        • Taube J.M.
        • Anders R.A.
        • Young G.D.
        • Xu H.
        • Sharma R.
        • McMiller T.L.
        • et al.
        Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape.
        Sci Transl Med. 2012; 4: 127ra37
        • Topalian S.L.
        • Drake C.G.
        • Pardoll D.M.
        Immune checkpoint blockade: a common denominator approach to cancer therapy.
        Cancer Cell. 2015; 27: 450-461
        • Barry M.
        • Bleackley R.C.
        Cytotoxic T lymphocytes: all roads lead to death.
        Nat Rev Immunol. 2002; 2: 401-409
        • Fridman W.H.
        • Pages F.
        • Sautes-Fridman C.
        • Garon J.
        The immune contexture in human tumours: impact on clinical outcome.
        Nat Rev Cancer. 2012; 12: 298-306
        • Al-Shibli K.I.
        • Donnem T.
        • Al-Saad S.
        • Persson M.
        • Bremnes R.M.
        • Busund L.T.
        Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer.
        Clin Cancer Res. 2008; 14: 5220-5227
        • Dieu-Nosjean M.C.
        • Antoine M.
        • Danel C.
        • Heudes D.
        • Wislez M.
        • Poulot V.
        • et al.
        Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures.
        J Clin Oncol. 2008; 26: 4410-4417
        • Hiraoka K.
        • Miyamoto M.
        • Cho Y.
        • Suzuoki M.
        • Oshikiri T.
        • Nakakubo Y.
        • et al.
        Concurrent infiltration by CD8t T cells and CD4t T cells is a favourable prognostic factor in non-small-cell lung carcinoma.
        Br J Cancer. 2006; 94: 275-280
        • Kawai O.
        • Ishii G.
        • Kubota K.
        • Murata Y.
        • Naito Y.
        • Mizuno T.
        • et al.
        Predominant infiltration of macrophages and CD8(t) T cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer.
        Cancer. 2008; 113: 1387-1395
        • Schalper K.A.
        • Brown J.
        • Carvajal-Hausdorf D.
        • McLaughlin J.
        • Velcheti V.
        • Syrigos K.N.
        • et al.
        Objective measurement and clinical significance of TILs in non–small cell lung cancer.
        JNCI J Natl Cancer Inst. 2015; 107: dju435
        • Donnem T.
        • Hald S.M.
        • Paulsen E.-E.
        • Richardsen E.
        • Al-Saad S.
        • Kilvaer T.K.
        • et al.
        Stromal CD8+ T-cell density—a promising supplement to TNM staging in non–small cell lung cancer.
        Clin Cancer Res. 2015; 21: 2635-2643
        • Kershaw M.H.
        • Teng M.W.
        • Smyth M.J.
        • Dancy P.K.
        Supernatural T cells: genetic modification of T cells for cancer therapy.
        Nat Rev Immunol. 2005; 5: 928-940
        • Young M.K.
        • Koh J.
        • Go H.
        • Go H.
        • Jeon Y.K.
        • Chung D.H.
        Clinicopathological analysis of PD-L1 and PD-L2 expression in pulmonary squamous cell carcinoma: comparison with tumor-infiltrating T cells and the status of oncogenic drivers.
        Lung Cancer. 2015; 88: 24-33
        • Sanmamed M.F.
        • Chen L.
        Inducible expression of B7-H1 (PD-L1) and its selective role in tumor site immune modulation.
        Cancer J. 2014; 20: 256-261
        • Zhang Y.
        • Huang S.
        • Gong D.
        • Qin Y.
        • Shen Q.
        Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer.
        Cell Mol Immunol. 2010; 7: 389-395
        • Galon J.
        • Mlecnik B.
        • Bindea G.
        • Angell H.K.
        • Berger A.
        • Lagorce C.
        • et al.
        Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours.
        J Pathol. 2014; 232: 199-209