Arantza Azpilikueta1, Jackeline Agorreta2, Sara Labiano1, José Luis Pérez-Gracia3, Alfonso R Sánchez-Paulete1, M Angela Aznar1, Daniel Ajona4, Ignacio Gil-Bazo3, Marta Larrayoz5, Alvaro Teijeira1, María E Rodriguez-Ruiz6, Ruben Pio4, Luis M Montuenga2, Ignacio Melero7. 1. Department of Immunology, Center for Applied Medical Research, Universidad de Navarra. 2. Program in Solid Tumors and Biomarkers, Center for Applied Medical Research, Universidad de Navarra; Department of Histology and Pathology, Universidad de Navarra. 3. Department of Oncology and Clinical Trial Unit, Clínica Universidad de Navarra. 4. Program in Solid Tumors and Biomarkers, Center for Applied Medical Research, Universidad de Navarra; Department of Biochemistry and Genetics, Universidad de Navarra. 5. Department of Immunology, Center for Applied Medical Research, Universidad de Navarra; Department of Histology and Pathology, Universidad de Navarra. 6. Program in Solid Tumors and Biomarkers, Center for Applied Medical Research, Universidad de Navarra. 7. Department of Immunology, Center for Applied Medical Research, Universidad de Navarra; Department of Oncology and Clinical Trial Unit, Clínica Universidad de Navarra. Electronic address: imelero@unav.es.
Abstract
INTRODUCTION: Anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (PD-L1) antagonist monoclonal antibodies (mAbs) against metastatic non-small cell lung cancer with special efficacy in patients with squamous cell lung cancer are being developed in the clinic. However, robust and reliable experimental models to test immunotherapeutic combinations in squamous lung tumors are still lacking. METHODS: We generated a transplantable squamous cell carcinoma cell line (UN-SCC680AJ) from a lung tumor induced by chronic N-nitroso-tris-chloroethylurea mutagenesis in A/J mice. Tumor cells expressed cytokeratins, overexpressed p40, and lacked thyroid transcription factor 1, confirming the squamous lineage reported by histological analysis. More than 200 mutations found in its exome suggested potential for antigenicity. Immunocompetent mice subcutaneously implanted with this syngeneic cell line were treated with anti-CD137 and/or anti-PD-1 mAbs and monitored for tumor growth/progression or assessed for intratumoral leukocyte infiltration using immunohistochemical analysis and flow cytometry. RESULTS: In syngeneic mice, large 12-day-established tumors derived from the transplantable cell line variant UN-SCC680AJ were amenable to curative treatment with anti-PD-1, anti-PD-L1, or anti-CD137 immunostimulatory mAbs. Single-agent therapies lost curative efficacy when treatment was started beyond day +17, whereas a combination of anti-PD-1 plus anti-CD137 achieved complete rejections. Tumor cells expressed weak baseline PD-L1 on the plasma membrane, but this could be readily induced by interferon-γ. Combined treatment efficacy required CD8 T cells and induced a leukocyte infiltrate in which T lymphocytes co-expressing CD137 and PD-1 were prominent. CONCLUSIONS: These promising results advocate the use of combined anti-PD-1/PD-L1 plus anti-CD137 mAb immunotherapy for the treatment of squamous non-small cell lung cancer in the clinical setting.
INTRODUCTION: Anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (PD-L1) antagonist monoclonal antibodies (mAbs) against metastatic non-small cell lung cancer with special efficacy in patients with squamous cell lung cancer are being developed in the clinic. However, robust and reliable experimental models to test immunotherapeutic combinations in squamous lung tumors are still lacking. METHODS: We generated a transplantable squamous cell carcinoma cell line (UN-SCC680AJ) from a lung tumor induced by chronic N-nitroso-tris-chloroethylurea mutagenesis in A/J mice. Tumor cells expressed cytokeratins, overexpressed p40, and lacked thyroid transcription factor 1, confirming the squamous lineage reported by histological analysis. More than 200 mutations found in its exome suggested potential for antigenicity. Immunocompetent mice subcutaneously implanted with this syngeneic cell line were treated with anti-CD137 and/or anti-PD-1 mAbs and monitored for tumor growth/progression or assessed for intratumoral leukocyte infiltration using immunohistochemical analysis and flow cytometry. RESULTS: In syngeneic mice, large 12-day-established tumors derived from the transplantable cell line variant UN-SCC680AJ were amenable to curative treatment with anti-PD-1, anti-PD-L1, or anti-CD137 immunostimulatory mAbs. Single-agent therapies lost curative efficacy when treatment was started beyond day +17, whereas a combination of anti-PD-1 plus anti-CD137 achieved complete rejections. Tumor cells expressed weak baseline PD-L1 on the plasma membrane, but this could be readily induced by interferon-γ. Combined treatment efficacy required CD8 T cells and induced a leukocyte infiltrate in which T lymphocytes co-expressing CD137 and PD-1 were prominent. CONCLUSIONS: These promising results advocate the use of combined anti-PD-1/PD-L1 plus anti-CD137 mAb immunotherapy for the treatment of squamous non-small cell lung cancer in the clinical setting.
Authors: Scott Gettinger; Jungmin Choi; Katherine Hastings; Anna Truini; Ila Datar; Ryan Sowell; Anna Wurtz; Weilai Dong; Guoping Cai; Mary Ann Melnick; Victor Y Du; Joseph Schlessinger; Sarah B Goldberg; Anne Chiang; Miguel F Sanmamed; Ignacio Melero; Jackeline Agorreta; Luis M Montuenga; Richard Lifton; Soldano Ferrone; Paula Kavathas; David L Rimm; Susan M Kaech; Kurt Schalper; Roy S Herbst; Katerina Politi Journal: Cancer Discov Date: 2017-10-12 Impact factor: 39.397
Authors: Iñaki Etxeberria; Elixabet Bolaños; Alvaro Teijeira; Saray Garasa; Alba Yanguas; Arantza Azpilikueta; William M Kavanaugh; Olga Vasiljeva; Marcia Belvin; Bruce Howng; Bryan Irving; Kimberly Tipton; James West; Li Mei; Alan J Korman; Emanuela Sega; Irene Olivera; Assunta Cirella; Maria C Ochoa; Maria E Rodriguez; Ana Melero; Miguel F Sanmamed; John J Engelhardt; Ignacio Melero Journal: Proc Natl Acad Sci U S A Date: 2021-06-29 Impact factor: 11.205