TY - JOUR
T1 - Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans
AU - Vicencio Bustamante, Jose
AU - Evans, Rachel
AU - Green, R
AU - An, Z
AU - Deng, Jinhai
AU - Treacy, Conor
AU - Mustapha, Rami
AU - Monypenny of Pitmilly, James
AU - Costoya , C
AU - Lawler, K
AU - Ng, K
AU - Desouza, Karen
AU - Coban, O
AU - Gomez, V
AU - Clancy, J
AU - Chen, SH
AU - Chalk, A
AU - Wong, F
AU - Gordon, P
AU - Savage, Courtney
AU - Gomes, C
AU - Pan, T
AU - Alfano, Giovanna
AU - Dolcetti, Luigi
AU - Chan, Julie Nuo En
AU - Florez-Borja , F
AU - Barber, Paul
AU - Weitsman, Gregory
AU - Sosnowska, D
AU - Capone, E
AU - Iacobelli, S
AU - Hochhauser, D
AU - Hartley, J
AU - Parsons, Madeline
AU - Arnold, James
AU - Ameer-Beg, Simon
AU - Quezada, Sergio A
AU - Yarden, Yosef
AU - Sala, G
AU - Ng, Tony
N1 - Funding Information:
We thank the Woodward laboratory for their kind donation of BioSTING. We thank Dr. Maria Lioumi (KCL) for strategic R&D management. We thank Dr. George Morrow (UCL, Cancer Institute, Flow Cytometry Core Facility) and Leanne Farnan (KCL, Guy?s & St. Thomas? NHS Foundation Trust, Flow Core Facility) for expert assistance with cell sorting equipment. This work was funded by a grant from Astra Zeneca (2015-7, JV, 10029191). This work was also supported by Cancer Research UK funding support to KCL/UCL Comprehensive Cancer Imaging Centre (CRUK & EPSRC, C1519/A16463; for KL, RE, and OC), Cancer Research UK King?s Health Partners Centre at King?s College London (RE and RM, C604/A25135), and Cancer Research UK UCL Centre (PRB, C7675/A29313); as well as CRUK City of London Centre (VG and CG, C7893/A26233). KN was supported by Cancer Research UK Clinical Training Fellowships (176885). LD is supported by EU IMI2 IMMUCAN (RE15612). JV and GA are supported by a CRUK Early Detection and Diagnosis Committee Project grant (C1519/A27375). CS and KD are supported by CRUK National Cancer Imaging Translational Accelerator grant (C1519/A28682). ZA and PG were supported by KCL Breast Cancer Now Research Unit grant. JNA holds a grant from CRUK (DCRPGF\100009) and a Cancer Research Institute/Wade FB Thompson CLIP grant (CRI3645). DS holds a CRUK Ph.D. studentship (C604/A27442).
Funding Information:
We thank the Woodward laboratory for their kind donation of BioSTING. We thank Dr. Maria Lioumi (KCL) for strategic R&D management. We thank Dr. George Morrow (UCL, Cancer Institute, Flow Cytometry Core Facility) and Leanne Farnan (KCL, Guy’s & St. Thomas’ NHS Foundation Trust, Flow Core Facility) for expert assistance with cell sorting equipment. This work was funded by a grant from Astra Zeneca (2015-7, JV, 10029191). This work was also supported by Cancer Research UK funding support to KCL/UCL Comprehensive Cancer Imaging Centre (CRUK & EPSRC, C1519/A16463; for KL, RE, and OC), Cancer Research UK King’s Health Partners Centre at King’s College London (RE and RM, C604/A25135), and Cancer Research UK UCL Centre (PRB, C7675/A29313); as well as CRUK City of London Centre (VG and CG, C7893/A26233). KN was supported by Cancer Research UK Clinical Training Fellowships (176885). LD is supported by EU IMI2 IMMUCAN (RE15612). JV and GA are supported by a CRUK Early Detection and Diagnosis Committee Project grant (C1519/A27375). CS and KD are supported by CRUK National Cancer Imaging Translational Accelerator grant (C1519/A28682). ZA and PG were supported by KCL Breast Cancer Now Research Unit grant. JNA holds a grant from CRUK (DCRPGF\100009) and a Cancer Research Institute/Wade FB Thompson CLIP grant (CRI3645). DS holds a CRUK Ph.D. studentship (C604/A27442).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/3/28
Y1 - 2022/3/28
N2 - Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.
AB - Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.
KW - Acrylamides
KW - Aniline Compounds/pharmacology
KW - Animals
KW - Antibodies, Monoclonal/pharmacology
KW - Carcinoma, Non-Small-Cell Lung/drug therapy
KW - Cell Line, Tumor
KW - Drug Resistance, Neoplasm
KW - Endoribonucleases
KW - ErbB Receptors/genetics
KW - Humans
KW - Lung Neoplasms/drug therapy
KW - Mice
KW - Mutation
KW - Neoplasm Recurrence, Local/drug therapy
KW - Nucleotidyltransferases
KW - Protein Kinase Inhibitors/pharmacology
KW - Protein Serine-Threonine Kinases
UR - http://www.scopus.com/inward/record.url?scp=85127235626&partnerID=8YFLogxK
U2 - 10.1038/s41419-022-04701-3
DO - 10.1038/s41419-022-04701-3
M3 - Article
C2 - 35347108
SN - 2041-4889
VL - 13
JO - Cell Death & Disease
JF - Cell Death & Disease
IS - 3
M1 - 274
ER -