Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade
| العنوان: | Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade |
|---|---|
| المؤلفون: | Paige Krystofinski, Jesse M. Zaretsky, Catherine S. Grasso, Gabriel Abril-Rodriguez, Antoni Ribas, Beata Berent-Maoz, Thomas Wohlwender, Anusha Kalbasi, Agustin Vega-Crespo, Siwen Hu-Lieskovan, Davis Y. Torrejon, Begoña Comin-Anduix, Giulia Parisi, Christopher M. Lee, Jennifer Tsoi, Katie M. Campbell, Gardenia Cheung-Lau, Ameya Champhekar, Pau Mascaro, Cristina Puig-Saus, Angel Garcia-Diaz |
| المصدر: | Digital.CSIC. Repositorio Institucional del CSIC instname Cancer discovery, vol 10, iss 8 Cancer Discov |
| بيانات النشر: | American Association for Cancer Research, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, CD4-Positive T-Lymphocytes, Programmed Cell Death 1 Receptor, Drug Resistance, CD8-Positive T-Lymphocytes, Inbred C57BL, Polyethylene Glycols, Mice, 0302 clinical medicine, Interferon, Loss of Function Mutation, Neoplasms, Cytotoxic T cell, Killer Cells, 2.1 Biological and endogenous factors, Aetiology, health care economics and organizations, Cancer, Tumor, Acquired immune system, Killer Cells, Natural, Oncology, 5.1 Pharmaceuticals, 030220 oncology & carcinogenesis, Natural, Development of treatments and therapeutic interventions, medicine.drug, Biotechnology, Agonist, Interleukin 2, medicine.drug_class, Oncology and Carcinogenesis, education, Biology, Article, Cell Line, 03 medical and health sciences, Clinical Research, Cell Line, Tumor, medicine, Animals, Humans, Gene knockout, Cell Proliferation, 5.2 Cellular and gene therapies, TLR9, Janus Kinase 1, Janus Kinase 2, Blockade, Mice, Inbred C57BL, 030104 developmental biology, Drug Resistance, Neoplasm, Toll-Like Receptor 9, Cancer research, Interleukin-2, Neoplasm, Interferons, beta 2-Microglobulin |
| الوصف: | Mechanism-based strategies to overcome resistance to PD-1 blockade therapy are urgently needed. We developed genetic acquired resistant models of JAK1, JAK2, and B2M loss-of-function mutations by gene knockout in human and murine cell lines. Human melanoma cell lines with JAK1/2 knockout became insensitive to IFN-induced antitumor effects, while B2M knockout was no longer recognized by antigen-specific T cells and hence was resistant to cytotoxicity. All of these mutations led to resistance to anti¿PD-1 therapy in vivo. JAK1/2-knockout resistance could be overcome with the activation of innate and adaptive immunity by intratumoral Toll-like receptor 9 agonist administration together with anti¿PD-1, mediated by natural killer (NK) and CD8 T cells. B2M-knockout resistance could be overcome by NK-cell and CD4 T-cell activation using the CD122 preferential IL2 agonist bempegaldesleukin. Therefore, mechanistically designed combination therapies can overcome genetic resistance to PD-1 blockade therapy. Significance: The activation of IFN signaling through pattern recognition receptors and the stimulation of NK cells overcome genetic mechanisms of resistance to PD-1 blockade therapy mediated through deficient IFN receptor and antigen presentation pathways. These approaches are being tested in the clinic to improve the antitumor activity of PD-1 blockade therapy. This study was funded in part by the Parker Institute for Cancer Immunotherapy, NIH grants R35 CA197633 and P01 CA244118, the Ressler Family Fund, and support from Ken and Donna Schultz (all to A. Ribas). D.Y. Torrejon was supported by a Young Investigator Award from ASCO, a grant from the Spanish Society of Medical Oncology for Translational Research in Reference Centers, and the V Foundation-Gil Nickel Family Endowed Fellowship in Melanoma Research. It has been developed within the framework of a medical doctorate at the Autonomous University of Barcelona. G. Abril-Rodriguez was supported by the Isabel & Harvey Kibel Fellowship Award and the Alan Ghitis Fellowship Award for Melanoma Research. J. Tsoi and K.M. Campbell were supported by the NIH Ruth L. Kirschstein Institutional National Research Service Award #T32-CA009120 and the UCLA Tumor Immunology Training Grant (T32CA009120). G. Parisi was supported by the V Foundation-Gil Nickel Family Endowed Fellowship in Melanoma Research. J.M. Zaretsky was in the UCLA Medical Scientist Training Program supported by NIH training grant GM08042. S. Hu-Lieskovan was supported by a Conquer Cancer Foundation ASCO Career Development Award, a UCLA KL2 Translational Research Award, and a Melanoma Research Alliance Young Investigator Award. Flow and mass cytometry were performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research Flow Cytometry Core Facility that is supported by NIH awards P30 CA016042 and 5P30 AI028697, and by the JCCC, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA. The purchase of the Helios mass cytometer that was used in this work was supported, in part, by funds provided by the James B. Pendleton Charitable Trust. We want to thank Dr. Cristiana Guiducci from Dynavax and Drs. Deborah Charych and Willem Overwijk from Nektar Therapeutics for helpful guidance in the performance of in vivo studies with SD-101 and bempegaldesleukin, respectively. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. |
| وصف الملف: | application/pdf |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::39588dd9d52bb82aac65e44c0517bfbeTest http://hdl.handle.net/10261/232405Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....39588dd9d52bb82aac65e44c0517bfbe |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |