BACKGROUND: Advancements in immunotherapeutic approaches only had a modest impact on the therapy of lung neuroendocrine neoplasms (LNENs). Our multicenter study aimed to investigate the expression patterns of novel immunotherapy targets in intermediate- and high-grade LNENs. METHODS: The expressions of V-domain Ig suppressor of T cell activation (VISTA), OX40L, Glucocorticoid-induced TNF receptor (GITR), and T cell immunoglobulin and mucin domain 3 (TIM3) proteins were measured by immunohistochemistry in surgically resected tumor samples of 26 atypical carcinoid (AC), 49 large cell neuroendocrine lung cancer (LCNEC), and 66 small cell lung cancer (SCLC) patients. Tumor and immune cells were separately scored. RESULTS: Tumor cell TIM3 expression was the highest in ACs (p < 0.001), whereas elevated tumor cell GITR levels were characteristic for both ACs and SCLCs (p < 0.001 and p = 0.011, respectively). OX40L expression of tumor cells was considerably lower in ACs (vs. SCLCs; p < 0.001). Tumor cell VISTA expression was consistently low in LNENs, with no significant differences across histological subtypes. ACs were the least immunogenic tumors concerning immune cell abundance (p < 0.001). Immune cell VISTA and GITR expressions were also significantly lower in these intermediate-grade malignancies than in SCLCs or in LCNECs. Immune cell TIM3 and GITR expressions were associated with borderline prognostic significance in our multivariate model (p = 0.057 and p = 0.071, respectively). CONCLUSIONS: LNEN subtypes have characteristic and widely divergent VISTA, OX40L, GITR, and TIM3 protein expressions. By shedding light on the different expression patterns of these immunotherapy targets, the current multicenter study provides support for the future implementation of novel immunotherapeutic approaches.

Center for Cancer Research Medical University of Vienna Vienna Austria

Department of Clinical Pharmacology National Institute of Oncology Chest and Abdominal Tumors Chemotherapy B Budapest Hungary

Department of Pathology University Hospital Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Physics of Complex Systems Eotvos Lorand University Budapest Hungary

Department of Pulmonary Diseases and Tuberculosis University Hospital Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Thoracic Surgery Comprehensive Cancer Center Vienna Medical University of Vienna Waehringer Guertel 18 20 1090 Vienna Austria

Department of Thoracic Surgery Semmelweis University and National Institute of Oncology Budapest Hungary

Department of Translational Medicine Lund University Lund Sweden

Diagnostic and Research Institute of Pathology Medical University of Graz Graz Austria

Division of Pulmonology Department of Medicine 2 Medical University of Vienna Vienna Austria

Division of Thoracic and Hyperbaric Surgery Department of Surgery Medical University of Graz Graz Austria

Medical Faculty Institute of Clinical and Molecular Pathology Palacky University Olomouc Olomouc Czech Republic

National Institute of Oncology and National Tumor Biology Laboratory Budapest Hungary

National Koranyi Institute of Pulmonology Budapest Hungary

Surgical Clinic University Hospital Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

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