Vanda Téglási1, Lilla Reiniger1, Katalin Fábián1, Orsolya Pipek1, Irén Csala1, Attila G Bagó1, Péter Várallyai1, Laura Vízkeleti1, Lívia Rojkó1, József Tímár1, Balázs Döme1, Zoltán Szállási1, Charles Swanton1, Judit Moldvay1. 1. First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary; MTA-SE NAP, Brain Metastasis Research Group, Hungarian Academy of Sciences, Second Department of Pathology, Semmelweis University, Budapest, Hungary; Department of Pulmonology, Semmelweis University, Budapest, Hungary; Department of Physics of Complex Systems, Eötvös Loránd University, Budapest, Hungary; Institute of Behavioural Sciences, Semmelweis University, Budapest, Hungary; Department of Neurooncology, National Institute of Clinical Neurosciences, Budapest, Hungary; Department of Radiology, National Institute of Clinical Neurosciences, Budapest, Hungary; Sixth Department of Pulmonology, National Korányi Institute of Pulmonology, Budapest, Hungary; Hungarian Academy of Sciences-Semmelweis University, Molecular Oncology Research Unit, Budapest, Hungary; Department of Tumor Biology, National Korányi Institute of Pulmonology-Semmelweis University, Budapest, Hungary; Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary; Division of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Children's Hospital Informatics Program at the Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts, USA; Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark; CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, London, UK; Francis Crick Institute, London, UK.
Abstract
BACKGROUND: Management of lung cancer patients who suffer from brain metastases represents a major challenge. Considering the promising results with immune checkpoint inhibitor treatment, evaluating the status of immune cell (IC) infiltrates in the prognosis of brain metastasis may lead to better therapeutic strategies with these agents. The aim of this study was to characterize the distribution of ICs and determine the expression of the checkpoint molecules programmed death protein 1 (PD-1) and its ligand, PD-L1, in brain metastasis of lung adenocarcinoma (LUAD) patients and to analyze their clinicopathological correlations. METHODS: We determined the presence of peritumoral mononuclear cells (mononuclear ring) and the density of intratumoral stromal mononuclear cells on brain metastasis tissue sections of 208 LUAD patients. PD-L1/PD-1 expressions were analyzed by immunohistochemistry. RESULTS: Mononuclear rings were significantly associated with better survival after brain metastasis surgery. Cases with massive stromal IC infiltration also showed a tendency for better overall survival. Lower expression of PD-1 and PD-L1 was associated with better survival in patients who underwent surgery for the primary tumor and had multiple brain metastases. Steroid administration and chemotherapy appear not to influence the density of IC in brain metastasis. CONCLUSION: This is the first study demonstrating the independent prognostic value of mononuclear rings in LUAD cases with brain metastasis. Our results also suggest that the density of tumor-associated ICs in addition to PD-L1 expression of tumor cells and ICs as well as PD-1 expression of ICs may hold relevant information for the appropriate selection of patients who might benefit from anti-PD-L1 or anti-PD-1 therapy.
BACKGROUND: Management of lung cancer patients who suffer from brain metastases represents a major challenge. Considering the promising results with immune checkpoint inhibitor treatment, evaluating the status of immune cell (IC) infiltrates in the prognosis of brain metastasis may lead to better therapeutic strategies with these agents. The aim of this study was to characterize the distribution of ICs and determine the expression of the checkpoint molecules programmed death protein 1 (PD-1) and its ligand, PD-L1, in brain metastasis of lung adenocarcinoma (LUAD) patients and to analyze their clinicopathological correlations. METHODS: We determined the presence of peritumoral mononuclear cells (mononuclear ring) and the density of intratumoral stromal mononuclear cells on brain metastasis tissue sections of 208 LUAD patients. PD-L1/PD-1 expressions were analyzed by immunohistochemistry. RESULTS: Mononuclear rings were significantly associated with better survival after brain metastasis surgery. Cases with massive stromal IC infiltration also showed a tendency for better overall survival. Lower expression of PD-1 and PD-L1 was associated with better survival in patients who underwent surgery for the primary tumor and had multiple brain metastases. Steroid administration and chemotherapy appear not to influence the density of IC in brain metastasis. CONCLUSION: This is the first study demonstrating the independent prognostic value of mononuclear rings in LUAD cases with brain metastasis. Our results also suggest that the density of tumor-associated ICs in addition to PD-L1 expression of tumor cells and ICs as well as PD-1 expression of ICs may hold relevant information for the appropriate selection of patients who might benefit from anti-PD-L1 or anti-PD-1 therapy.
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