An immune gene expression signature distinguishes central nervous system metastases from primary tumours in non–small-cell lung cancer

Georgios Tsakonas,Rolf Lewensohn,Johan Botling,Cristian Ortiz-Villalon,Patrick Micke,Signe Friesland,Helena Nord,Magnus Lindskog,Martin Sandelin,Per Hydbring,Simon Ekman

doi:10.1016/j.ejca.2020.03.014

Georgios Tsakonas, Rolf Lewensohn + Show 9 more

Open Access

https://doi.org/10.1016/j.ejca.2020.03.014

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Abstract

BackgroundDissemination of non–small-cell lung cancer (NSCLC) in the central nervous system is a frequent and challenging clinical problem. Systemic or local therapies rarely prolong survival and have modest activity regarding local control. Alterations in gene expression in brain metastasis versus primary tumour may increase aggressiveness and impair therapeutic efforts. MethodsWe identified 25 patients with surgically removed NSCLC brain metastases in two different patient cohorts. For 13 of these patients, primary tumour samples were available. Gene expression analysis using the nCounter® PanCancer Immune Profiling gene expression panel (nanoString technologies Inc.) was performed in brain metastases and primary tumour samples. Identification of differentially expressed genes was conducted on normalized data using the nSolver analysis software. ResultsWe compared gene expression patterns in brain metastases with primary tumours. Brain metastasis samples displayed a distinct clustering pattern compared to primary tumour samples with a statistically significant downregulation of genes related to immune response and immune cell activation. Results from KEGG term analysis on differentially expressed genes revealed a concomitant enrichment of multiple KEGG terms associated with the immune system. We identified a 12-gene immune signature that clearly separated brain metastases from primary tumours. ConclusionsWe identified a unique gene downregulation pattern in brain metastases compared with primary tumours. This finding may explain the lower intracranial efficacy of systemic therapy, especially immunotherapy, in brain metastasis of patients with NSCLC.

Highlights

Brain metastases (BMs) are common in advanced nonesmall-ecell lung cancer (NSCLC) [1]
A unique gene downregulation pattern in the brain metastatic setting was identified in this cohort of patients with matched gene expression analyses from primary lung cancer and brain metastasis
We observed statistically significant downregulation of several genes encoding for checkpoint proteins, including PDCD1, CTLA4, LAG3 and ICOS [18], all with >3 fold-expression in primary tumour compared to BM (Supplemental Table 3)

Summary

Introduction

Brain metastases (BMs) are common in advanced nonesmall-ecell lung cancer (NSCLC) [1]. Prognosis is significantly better in patients with oncogenic-driven tumours and BM, where high response rates and prolonged survival can be achieved with the use of targeted therapies, including against EGFR and ALK [5,6]. Immunotherapy using immune checkpoint inhibitors (ICIs) has started a new era of treatment for lung cancer Numerous studies in both second and first line have demonstrated improved survival of patients with NSCLC receiving PD-1/PD-L1 inhibitors versus chemotherapy [11e13] or in combination with chemotherapy versus chemotherapy in first-line [14,15]. Results: We compared gene expression patterns in brain metastases with primary tumours.

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