Cancer Immunology, Immunotherapy

, Volume 65, Issue 1, pp 1–11 | Cite as

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

  • Philipp Müller
  • Sacha I. Rothschild
  • Walter Arnold
  • Petra Hirschmann
  • Lukas Horvath
  • Lukas Bubendorf
  • Spasenija Savic
  • Alfred Zippelius
Original Article


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.


Non-small cell lung cancer Primary tumor Metastasis Immune cells Anti-tumor immunity 



Non-small cell lung cancer



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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

262_2015_1768_MOESM1_ESM.pdf (137 kb)
Supplementary material 1 (PDF 137 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Philipp Müller
    • 1
  • Sacha I. Rothschild
    • 1
    • 2
  • Walter Arnold
    • 3
  • Petra Hirschmann
    • 4
  • Lukas Horvath
    • 1
  • Lukas Bubendorf
    • 4
  • Spasenija Savic
    • 4
  • Alfred Zippelius
    • 1
    • 2
  1. 1.Department of Biomedicine, Cancer Immunology and BiologyUniversity Hospital and University of BaselBaselSwitzerland
  2. 2.Department of Internal Medicine, Medical OncologyUniversity Hospital BaselBaselSwitzerland
  3. 3.Institute for PathologyCantonal Hospital LucerneLucerneSwitzerland
  4. 4.Institute for PathologyUniversity Hospital BaselBaselSwitzerland

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