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Metastatic spread in patients with non-small cell lung cancer is associated with a reduced density of tumor-infiltrating T cells

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Abstract

Tumor-infiltrating lymphocytes play an important role in cell-mediated immune destruction of cancer cells and tumor growth control. We investigated the heterogeneity of immune cell infiltrates between primary non-small cell lung carcinomas (NSCLC) and corresponding metastases. Formalin-fixed, paraffin-embedded primary tumors and corresponding metastases from 34 NSCLC patients were analyzed by immunohistochemistry for CD4, CD8, CD11c, CD68, CD163 and PD-L1. The percentage of positively stained cells within the stroma and tumor cell clusters was recorded and compared between primary tumors and metastases. We found significantly fewer CD4+ and CD8+ T cells within tumor cell clusters as compared with the stromal compartment, both in primary tumors and corresponding metastases. CD8+ T cell counts were significantly lower in metastatic lesions than in the corresponding primary tumors, both in the stroma and the tumor cell islets. Of note, the CD8/CD4 ratio was significantly reduced in metastatic lesions compared with the corresponding primary tumors in tumor cell islets, but not in the stroma. We noted significantly fewer CD11c+ cells and CD68+ as well as CD163+ macrophages in tumor cell islets compared with the tumor stroma, but no difference between primary and metastatic lesions. Furthermore, the CD8/CD68 ratio was higher in primary tumors than in the corresponding metastases. We demonstrate a differential pattern of immune cell infiltration in matched primary and metastatic NSCLC lesions, with a significantly lower density of CD8+ T cells in metastatic lesions compared with the primary tumors. The lower CD8/CD4 and CD8/CD68 ratios observed in metastases indicate a rather tolerogenic and tumor-promoting microenvironment at the metastatic site.

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Abbreviations

NSCLC:

Non-small cell lung cancer

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Acknowledgments

This work was supported by grants from the Swiss National Science Foundation, the Wilhelm Sander-Foundation, the Cancer League Basel, the Huggenberger-Bischoff Foundation for Cancer Research, the Research Fonds of the University Basel and the Freiwillige Akademische Gesellschaft Basel.

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    Authors and Affiliations

    1. Department of Biomedicine, Cancer Immunology and Biology, University Hospital and University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland

      Philipp Müller, Sacha I. Rothschild, Lukas Horvath & Alfred Zippelius

    2. Department of Internal Medicine, Medical Oncology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland

      Sacha I. Rothschild & Alfred Zippelius

    3. Institute for Pathology, Cantonal Hospital Lucerne, Lucerne, Switzerland

      Walter Arnold

    4. Institute for Pathology, University Hospital Basel, Basel, Switzerland

      Petra Hirschmann, Lukas Bubendorf & Spasenija Savic

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    Philipp Müller and Sacha I. Rothschild have contributed equally to this work.

    Spasenija Savic and Alfred Zippelius have contributed equally to this work.

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    Müller, P., Rothschild, S.I., Arnold, W. et al. Metastatic spread in patients with non-small cell lung cancer is associated with a reduced density of tumor-infiltrating T cells. Cancer Immunol Immunother 65, 1–11 (2016). https://doi.org/10.1007/s00262-015-1768-3

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