Portia L Thomas1, Sarah M Groves2, Yun-Kai Zhang3, Jia Li4, Paula Gonzalez-Ericsson5, Shamilene Sivagnanam6, Courtney B Betts6, Hua-Chang Chen4, Qi Liu4, Cindy Lowe7, Heidi Chen4, Kelli L Boyd7, Prasad R Kopparapu3, Yingjun Yan3, Lisa M Coussens6, Vito Quaranta2, Darren R Tyson2, Wade Iams3, Christine M Lovly8. 1. Department of Microbiology, Immunology & Physiology, School of Medicine, Meharry Medical College, Nashville, Tennessee; School of Graduate Studies & Research, Meharry Medical College, Nashville, Tennessee. 2. Department of Biochemistry, Vanderbilt University, Nashville, Tennessee. 3. Division of Hematology-Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. 4. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee. 5. Breast Cancer Research Program, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee. 6. Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon. 7. Department of Pathology, Immunology and Microbiology, Vanderbilt University Medical Center, Nashville, Tennessee. 8. School of Graduate Studies & Research, Meharry Medical College, Nashville, Tennessee; Division of Hematology-Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: christine.lovly@vumc.org.
Abstract
INTRODUCTION: The programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors, atezolizumab and durvalumab, have received regulatory approval for the first-line treatment of patients with extensive-stage SCLC. Nevertheless, when used in combination with platinum-based chemotherapy, these PD-L1 inhibitors only improve overall survival by 2 to 3 months. This may be due to the observation that less than 20% of SCLC tumors express PD-L1 at greater than 1%. Evaluating the composition and abundance of checkpoint molecules in SCLC may identify molecules beyond PD-L1 that are amenable to therapeutic targeting. METHODS: We analyzed RNA-sequencing data from SCLC cell lines (n = 108) and primary tumor specimens (n = 81) for expression of 39 functionally validated inhibitory checkpoint ligands. Furthermore, we generated tissue microarrays containing SCLC cell lines and patient with SCLC specimens to confirm expression of these molecules by immunohistochemistry. We annotated patient outcomes data, including treatment response and overall survival. RESULTS: The checkpoint protein B7-H6 (NCR3LG1) exhibited increased protein expression relative to PD-L1 in cell lines and tumors (p < 0.05). Higher B7-H6 protein expression correlated with longer progression-free survival (p = 0.0368) and increased total immune infiltrates (CD45+) in patients. Furthermore, increased B7-H6 gene expression in SCLC tumors correlated with a decreased activated natural killer cell gene signature, suggesting a complex interplay between B7-H6 expression and immune signature in SCLC. CONCLUSIONS: We investigated 39 inhibitory checkpoint molecules in SCLC and found that B7-H6 is highly expressed and associated with progression-free survival. In addition, 26 of 39 immune checkpoint proteins in SCLC tumors were more abundantly expressed than PD-L1, indicating an urgent need to investigate additional checkpoint targets for therapy in addition to PD-L1. Published by Elsevier Inc.
INTRODUCTION: The programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors, atezolizumab and durvalumab, have received regulatory approval for the first-line treatment of patients with extensive-stage SCLC. Nevertheless, when used in combination with platinum-based chemotherapy, these PD-L1 inhibitors only improve overall survival by 2 to 3 months. This may be due to the observation that less than 20% of SCLC tumors express PD-L1 at greater than 1%. Evaluating the composition and abundance of checkpoint molecules in SCLC may identify molecules beyond PD-L1 that are amenable to therapeutic targeting. METHODS: We analyzed RNA-sequencing data from SCLC cell lines (n = 108) and primary tumor specimens (n = 81) for expression of 39 functionally validated inhibitory checkpoint ligands. Furthermore, we generated tissue microarrays containing SCLC cell lines and patient with SCLC specimens to confirm expression of these molecules by immunohistochemistry. We annotated patient outcomes data, including treatment response and overall survival. RESULTS: The checkpoint protein B7-H6 (NCR3LG1) exhibited increased protein expression relative to PD-L1 in cell lines and tumors (p < 0.05). Higher B7-H6 protein expression correlated with longer progression-free survival (p = 0.0368) and increased total immune infiltrates (CD45+) in patients. Furthermore, increased B7-H6 gene expression in SCLC tumors correlated with a decreased activated natural killer cell gene signature, suggesting a complex interplay between B7-H6 expression and immune signature in SCLC. CONCLUSIONS: We investigated 39 inhibitory checkpoint molecules in SCLC and found that B7-H6 is highly expressed and associated with progression-free survival. In addition, 26 of 39 immune checkpoint proteins in SCLC tumors were more abundantly expressed than PD-L1, indicating an urgent need to investigate additional checkpoint targets for therapy in addition to PD-L1. Published by Elsevier Inc.
Entities:
Keywords:
B7-H6; Checkpoint molecules; Immune checkpoint inhibitor; Immunotherapy; Small cell lung cancer (SCLC)
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