Zoltan Lohinai1, Balazs Dome2,3,4,5, David Dora6, Christopher Rivard7, Hui Yu7, Shivaun Lueke Pickard7, Viktoria Laszlo8,9,10, Tunde Harko8, Zsolt Megyesfalvi8,9,10, Csongor Gerdan8,11, Elek Dinya12, Konrad Hoetzenecker9, Fred R Hirsch7,13. 1. Department of Tumor Biology, National Koranyi Institute of Pulmonology, 1121, Piheno ut 1., Budapest, Hungary. zoltan.lohinai@koranyi.hu. 2. Department of Tumor Biology, National Koranyi Institute of Pulmonology, 1121, Piheno ut 1., Budapest, Hungary. balazs.dome@meduniwien.ac.at. 3. Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. balazs.dome@meduniwien.ac.at. 4. Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary. balazs.dome@meduniwien.ac.at. 5. Department of Translational Medicine, Lund University, Lund, Sweden. balazs.dome@meduniwien.ac.at. 6. Department of Anatomy, Histology, and Embryology, Faculty of Medicine, Semmelweis University, Budapest, Hungary. 7. Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. 8. Department of Tumor Biology, National Koranyi Institute of Pulmonology, 1121, Piheno ut 1., Budapest, Hungary. 9. Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. 10. Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary. 11. Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary. 12. Institute of Digital Health Sciences, Faculty of Public Services, Semmelweis University, Budapest, Hungary. 13. Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai Health System, New York, NY, USA.
Abstract
BACKGROUND: SCLC is an aggressive malignancy where immunotherapies show limited efficacy. We aimed to characterize the SCLC microenvironment according to the expression patterns of SCLC subtype markers and novel immune checkpoints to identify therapeutic vulnerabilities. METHODS: We included SCLC tissue samples from 219 surgically resected, limited-stage patients in this cross-sectional study. We performed immunohistochemistry for STING and MHCII, as well as for the novel subtype markers (ASCL1, NEUROD1, POU2F3, YAP1). Moreover, we assessed CD45 + , CD8 + and CD68 + immune cell infiltration. RESULTS: 36% of SCLC tumors showed significant stromal or intraepithelial CD45 + immune cell infiltration. These patients exhibited significantly increased overall survival (OS) (vs. patients with immune-deserted tumors). High CD8 expression was associated with increased median OS. We found STING expression on cancer-associated fibroblasts in the stroma and on T-cells and macrophages in both tumorous and stromal compartments. STING expression positively correlated with immune cell infiltration. Increased STING-positivity in tumor nests was an independent favorable prognosticator for OS. ASCL1 was the most frequently expressed subtype-specific protein. Concomitant expression of three or four subtype-defining markers was seen in 13.8% of the included samples, whereas 24.1% of the cases were classified as quadruple negative tumors. YAP1 expression was associated with increased immune infiltrates. Tumor cell MHCII expression positively correlated with immune cell infiltration and with STING- and YAP1 expressions. CONCLUSIONS: STING and MHCII are expressed in SCLC. The majority of immune-infiltrated SCLCs exhibit increased STING expression. Immune infiltration and STING expression are prognostic in limited-stage SCLC, making STING a potential therapeutic target.
BACKGROUND: SCLC is an aggressive malignancy where immunotherapies show limited efficacy. We aimed to characterize the SCLC microenvironment according to the expression patterns of SCLC subtype markers and novel immune checkpoints to identify therapeutic vulnerabilities. METHODS: We included SCLC tissue samples from 219 surgically resected, limited-stage patients in this cross-sectional study. We performed immunohistochemistry for STING and MHCII, as well as for the novel subtype markers (ASCL1, NEUROD1, POU2F3, YAP1). Moreover, we assessed CD45 + , CD8 + and CD68 + immune cell infiltration. RESULTS: 36% of SCLC tumors showed significant stromal or intraepithelial CD45 + immune cell infiltration. These patients exhibited significantly increased overall survival (OS) (vs. patients with immune-deserted tumors). High CD8 expression was associated with increased median OS. We found STING expression on cancer-associated fibroblasts in the stroma and on T-cells and macrophages in both tumorous and stromal compartments. STING expression positively correlated with immune cell infiltration. Increased STING-positivity in tumor nests was an independent favorable prognosticator for OS. ASCL1 was the most frequently expressed subtype-specific protein. Concomitant expression of three or four subtype-defining markers was seen in 13.8% of the included samples, whereas 24.1% of the cases were classified as quadruple negative tumors. YAP1 expression was associated with increased immune infiltrates. Tumor cell MHCII expression positively correlated with immune cell infiltration and with STING- and YAP1 expressions. CONCLUSIONS: STING and MHCII are expressed in SCLC. The majority of immune-infiltrated SCLCs exhibit increased STING expression. Immune infiltration and STING expression are prognostic in limited-stage SCLC, making STING a potential therapeutic target.
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