Thomas A Mace1, Reena Shakya2, Jason R Pitarresi3, Benjamin Swanson4, Christopher W McQuinn1, Shannon Loftus1, Emily Nordquist1, Zobeida Cruz-Monserrate1, Lianbo Yu5, Gregory Young6, Xiaoling Zhong7, Teresa A Zimmers7, Michael C Ostrowski3, Thomas Ludwig3, Mark Bloomston8, Tanios Bekaii-Saab9, Gregory B Lesinski10. 1. Divisions of Medical Oncology and Gastroenterology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA. 2. Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA. 3. Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, USA. 4. Department of Pathology, The Ohio State University, Columbus, Ohio, USA. 5. Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA. 6. Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA. 7. Department of Surgery (Indiana University) and IU Simon Cancer Center, The Ohio State University, Columbus, Ohio, USA. 8. Division of Surgical Oncology, Department of Surgery, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio, USA. 9. Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, Arizona, USA. 10. Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
Abstract
OBJECTIVE: Limited efficacy of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) has prompted investigation into combination therapy. We hypothesised that interleukin 6 (IL-6) blockade would modulate immunological features of PDAC and enhance the efficacy of anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor therapy. DESIGN: Transcription profiles and IL-6 secretion from primary patient-derived pancreatic stellate cells (PSCs) were analyzed via Nanostring and immunohistochemistry, respectively. In vivo efficacy and mechanistic studies were conducted with antibodies (Abs) targeting IL-6, PD-L1, CD4 or CD8 in subcutaneous or orthotopic models using Panc02, MT5 or KPC-luc cell lines; and the aggressive, genetically engineered PDAC model (KrasLSL-G12D, Trp53LSL-R270H, Pdx1-cre, Brca2F/F (KPC-Brca2 mice)). Systemic and local changes in immunophenotype were measured by flow cytometry or immunohistochemical analysis. RESULTS: PSCs (n=12) demonstrated prominent IL-6 expression, which was localised to stroma of tumours. Combined IL-6 and PD-L1 blockade elicited efficacy in mice bearing subcutaneous MT5 (p<0.02) and Panc02 tumours (p=0.046), which was accompanied by increased intratumoural effector T lymphocytes (CD62L-CD44-). CD8-depleting but not CD4-depleting Abs abrogated the efficacy of combined IL-6 and PD-L1 blockade in mice bearing Panc02 tumours (p=0.0016). This treatment combination also elicited significant antitumour activity in mice bearing orthotopic KPC-luc tumours and limited tumour progression in KPC-Brca2 mice (p<0.001). Histological analysis revealed increased T-cell infiltration and reduced α-smooth muscle actin cells in tumours from multiple models. Finally, IL-6 and PD-L1 blockade increased overall survival in KPC-Brca2 mice compared with isotype controls (p=0.0012). CONCLUSIONS: These preclinical results indicate that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in PDAC. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
OBJECTIVE: Limited efficacy of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) has prompted investigation into combination therapy. We hypothesised that interleukin 6 (IL-6) blockade would modulate immunological features of PDAC and enhance the efficacy of anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor therapy. DESIGN: Transcription profiles and IL-6 secretion from primary patient-derived pancreatic stellate cells (PSCs) were analyzed via Nanostring and immunohistochemistry, respectively. In vivo efficacy and mechanistic studies were conducted with antibodies (Abs) targeting IL-6, PD-L1, CD4 or CD8 in subcutaneous or orthotopic models using Panc02, MT5 or KPC-luc cell lines; and the aggressive, genetically engineered PDAC model (KrasLSL-G12D, Trp53LSL-R270H, Pdx1-cre, Brca2F/F (KPC-Brca2mice)). Systemic and local changes in immunophenotype were measured by flow cytometry or immunohistochemical analysis. RESULTS: PSCs (n=12) demonstrated prominent IL-6 expression, which was localised to stroma of tumours. Combined IL-6 and PD-L1 blockade elicited efficacy in mice bearing subcutaneous MT5 (p<0.02) and Panc02 tumours (p=0.046), which was accompanied by increased intratumoural effector T lymphocytes (CD62L-CD44-). CD8-depleting but not CD4-depleting Abs abrogated the efficacy of combined IL-6 and PD-L1 blockade in mice bearing Panc02 tumours (p=0.0016). This treatment combination also elicited significant antitumour activity in mice bearing orthotopic KPC-luc tumours and limited tumour progression in KPC-Brca2mice (p<0.001). Histological analysis revealed increased T-cell infiltration and reduced α-smooth muscle actin cells in tumours from multiple models. Finally, IL-6 and PD-L1 blockade increased overall survival in KPC-Brca2mice compared with isotype controls (p=0.0012). CONCLUSIONS: These preclinical results indicate that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in PDAC. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Entities:
Keywords:
IMMUNOTHERAPY; INTERLEUKINS; PANCREATIC CANCER
Authors: Albert Lo; Liang-Chuan S Wang; Steven M Albelda; Ellen Puré; John Scholler; James Monslow; Diana Avery; Kheng Newick; Shaun O'Brien; Rebecca A Evans; David J Bajor; Cynthia Clendenin; Amy C Durham; Elizabeth L Buza; Robert H Vonderheide; Carl H June Journal: Cancer Res Date: 2015-05-15 Impact factor: 12.701
Authors: Marina Lesina; Magdalena U Kurkowski; Katharina Ludes; Stefan Rose-John; Matthias Treiber; Günter Klöppel; Akihiko Yoshimura; Wolfgang Reindl; Bence Sipos; Shizuo Akira; Roland M Schmid; Hana Algül Journal: Cancer Cell Date: 2011-04-12 Impact factor: 31.743
Authors: Rachel F Gabitass; Nicola E Annels; Deborah D Stocken; Hardev A Pandha; Gary W Middleton Journal: Cancer Immunol Immunother Date: 2011-06-05 Impact factor: 6.968
Authors: Matthew R Farren; Thomas A Mace; Susan Geyer; Sameh Mikhail; Christina Wu; Kristen Ciombor; Sanaa Tahiri; Daniel Ahn; Anne M Noonan; Miguel Villalona-Calero; Tanios Bekaii-Saab; Gregory B Lesinski Journal: Clin Cancer Res Date: 2015-12-30 Impact factor: 12.531
Authors: Bethany L Mundy-Bosse; Gregory S Young; Todd Bauer; Elaine Binkley; Mark Bloomston; Matthew A Bill; Tanios Bekaii-Saab; William E Carson; Gregory B Lesinski Journal: Cancer Immunol Immunother Date: 2011-05-21 Impact factor: 6.968
Authors: Roy S Herbst; Jean-Charles Soria; Marcin Kowanetz; Gregg D Fine; Omid Hamid; Michael S Gordon; Jeffery A Sosman; David F McDermott; John D Powderly; Scott N Gettinger; Holbrook E K Kohrt; Leora Horn; Donald P Lawrence; Sandra Rost; Maya Leabman; Yuanyuan Xiao; Ahmad Mokatrin; Hartmut Koeppen; Priti S Hegde; Ira Mellman; Daniel S Chen; F Stephen Hodi Journal: Nature Date: 2014-11-27 Impact factor: 49.962
Authors: Sally A Hunsucker; Valeria Magarotto; Deborah J Kuhn; Steven M Kornblau; Michael Wang; Donna M Weber; Sheeba K Thomas; Jatin J Shah; Peter M Voorhees; Hong Xie; Mark Cornfeld; Jeffrey A Nemeth; Robert Z Orlowski Journal: Br J Haematol Date: 2011-01-17 Impact factor: 6.998
Authors: Yuxin Wang; Anette H H van Boxel-Dezaire; HyeonJoo Cheon; Jinbo Yang; George R Stark Journal: Proc Natl Acad Sci U S A Date: 2013-09-30 Impact factor: 11.205
Authors: Maureen A Sartor; Craig R Tomlinson; Scott C Wesselkamper; Siva Sivaganesan; George D Leikauf; Mario Medvedovic Journal: BMC Bioinformatics Date: 2006-12-19 Impact factor: 3.169
Authors: Alyssa D Smith; Chunwan Lu; Daniela Payne; Amy V Paschall; John D Klement; Priscilla S Redd; Mohammed L Ibrahim; Dafeng Yang; Qimei Han; Zhuoqi Liu; Huidong Shi; Thomas J Hartney; Asha Nayak-Kapoor; Kebin Liu Journal: Cancer Res Date: 2020-06-17 Impact factor: 12.701
Authors: Alex Reza Gholiha; Peter Hollander; Ingrid Glimelius; Gustaf Hedstrom; Daniel Molin; Henrik Hjalgrim; Karin E Smedby; Jamileh Hashemi; Rose-Marie Amini; Gunilla Enblad Journal: Blood Adv Date: 2021-03-23
Authors: Kristen B Long; Graham Tooker; Evan Tooker; Santiago Lombo Luque; Jae W Lee; Xiaoqing Pan; Gregory L Beatty Journal: Mol Cancer Ther Date: 2017-06-13 Impact factor: 6.261
Authors: Giulia Biffi; Tobiloba E Oni; Benjamin Spielman; Yuan Hao; Ela Elyada; Youngkyu Park; Jonathan Preall; David A Tuveson Journal: Cancer Discov Date: 2018-10-26 Impact factor: 39.397
Authors: Guido Eibl; Zobeida Cruz-Monserrate; Murray Korc; Maxim S Petrov; Mark O Goodarzi; William E Fisher; Aida Habtezion; Aurelia Lugea; Stephen J Pandol; Phil A Hart; Dana K Andersen Journal: J Acad Nutr Diet Date: 2017-09-12 Impact factor: 4.910