title: Metastatic spread in patients with non-small cell lung cancer is associated with a reduced density of tumor-infiltrating T cells.
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.
authors.affiliation: Department of Biomedicine, Cancer Immunology and Biology, University Hospital and University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland. ph.mueller@unibas.ch.
authors.forename: Philipp
authors.initials: P
authors.lastname: Müller
authors.affiliation: Department of Biomedicine, Cancer Immunology and Biology, University Hospital and University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland.|Department of Internal Medicine, Medical Oncology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.
authors.forename: Sacha I
authors.initials: SI
authors.lastname: Rothschild
authors.affiliation: Institute for Pathology, Cantonal Hospital Lucerne, Lucerne, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Arnold
authors.affiliation: Institute for Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Hirschmann
authors.affiliation: Department of Biomedicine, Cancer Immunology and Biology, University Hospital and University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Horvath
authors.affiliation: Institute for Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Bubendorf
authors.affiliation: Institute for Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Spasenija
authors.initials: S
authors.lastname: Savic
authors.affiliation: Department of Biomedicine, Cancer Immunology and Biology, University Hospital and University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland. alfred.zippelius@usb.ch.|Department of Internal Medicine, Medical Oncology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland. alfred.zippelius@usb.ch.
authors.forename: Alfred
authors.initials: A
authors.lastname: Zippelius
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D009362:Neoplasm Metastasis; D011379:Prognosis; D059016:Tumor Microenvironment
keywords: Anti-tumor immunity; Immune cells; Metastasis; Non-small cell lung cancer; Primary tumor