Unexpected PD‐L1 immune evasion mechanism in TNBC, ovarian, and other solid tumors by DR5 agonist antibodies
Open Access
- 15 February 2021
- journal article
- research article
- Published by EMBO in EMBO Molecular Medicine
- Vol. 13 (3), e12716
- https://doi.org/10.15252/emmm.202012716
Abstract
Lack of effective immune infiltration represents a significant barrier to immunotherapy in solid tumors. Thus, solid tumor‐enriched death receptor‐5 (DR5) activating antibodies, which generates tumor debulking by extrinsic apoptotic cytotoxicity, remains a crucial alternate therapeutic strategy. Over past few decades, many DR5 antibodies moved to clinical trials after successfully controlling tumors in immunodeficient tumor xenografts. However, DR5 antibodies failed to significantly improve survival in phase‐II trials, leading in efforts to generate second generation of DR5 agonists to supersize apoptotic cytotoxicity in tumors. Here we have discovered that clinical DR5 antibodies activate an unexpected immunosuppressive PD‐L1 stabilization pathway, which potentially had contributed to their limited success in clinics. The DR5 agonist stimulated caspase‐8 signaling not only activates ROCK1 but also undermines proteasome function, both of which contributes to increased PD‐L1 stability on tumor cell surface. Targeting DR5‐ROCK1‐PD‐L1 axis markedly increases immune effector T‐cell function, promotes tumor regression, and improves overall survival in animal models. These insights have identified a potential clinically viable combinatorial strategy to revive solid cancer immunotherapy using death receptor agonism.Funding Information
- U.S. Department of Defense (BC17097,W81XWH‐18‐1‐0048, OC180412,W81XWH‐19‐1‐0190, BC17097P1,W81XWH‐18‐1‐0049)
This publication has 75 references indexed in Scilit:
- Apoptotic and antitumor activity of death receptor antibodies require inhibitory Fcγ receptor engagementProceedings of the National Academy of Sciences of the United States of America, 2012
- Biogenesis of the Posterior Pole Is Mediated by the Exosome/Microvesicle Protein-sorting PathwayOnline Journal of Public Health Informatics, 2011
- TGFβ/TNFα-Mediated Epithelial–Mesenchymal Transition Generates Breast Cancer Stem Cells with a Claudin-Low PhenotypeCancer Research, 2011
- Phase I Trial of Weekly Tigatuzumab, an Agonistic Humanized Monoclonal Antibody Targeting Death Receptor 5 (DR5)Cancer Biotherapy & Radiopharmaceuticals, 2010
- Death receptor 5 mediated-apoptosis contributes to cholestatic liver diseaseProceedings of the National Academy of Sciences of the United States of America, 2008
- Apomab: An agonist monoclonal antibody directed against Death Receptor 5/TRAIL-Receptor 2 for use in the treatment of solid tumorsExpert Opinion on Biological Therapy, 2008
- To kill a tumor cell: the potential of proapoptotic receptor agonistsJCI Insight, 2008
- Caspase inactivation of the proteasomeCell Death & Differentiation, 2005
- Enhanced Apoptosis and Tumor Regression Induced by a Direct Agonist Antibody to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Receptor 2Clinical Cancer Research, 2005
- Selection for TRAIL resistance results in melanoma cells with high proliferative potentialFEBS Letters, 2005