The target antigen determines the mechanism of acquired resistance to T cell-based therapies
| Autor: | Alex Martínez-Sabadell, Beatriz Morancho, Irene Rius Ruiz, Macarena Román Alonso, Pablo Ovejero Romero, Marta Escorihuela, Irene Chicote, Hector G. Palmer, Lara Nonell, Mercè Alemany-Chavarria, Christian Klein, Marina Bacac, Joaquín Arribas, Enrique J. Arenas |
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| Přispěvatelé: | Institut Català de la Salut, [Martínez-Sabadell A] Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer, Monforte de Lemos, Madrid, Spain. Cancer Research Program, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Morancho B, Román Alonso M, Ovejero Romero P, Escorihuela M] Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Rius Ruiz I, Arenas EJ] Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer, Monforte de Lemos, Madrid, Spain. [Arribas J] Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer, Monforte de Lemos, Madrid, Spain. Cancer Research Program, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain. Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Rok vydání: | 2021 |
| Předmět: |
Cèl·lules T - Receptors
T-Lymphocytes Resistance Receptors Antigen T-Cell Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] 5-AZA T cell bispecific antibody Other subheadings::Other subheadings::/drug therapy [Other subheadings] General Biochemistry Genetics and Molecular Biology neoplasias [ENFERMEDADES] Interferon-gamma CEA HER2 Cell Line Tumor Antibodies Bispecific Humans Cells::Blood Cells::Leukocytes::Leukocytes Mononuclear::Lymphocytes::T-Lymphocytes [ANATOMY] Cancer Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy [ANALYTICAL DIAGNOSTIC AND THERAPEUTIC TECHNIQUES AND EQUIPMENT] terapéutica::terapia biológica::inmunomodulación::inmunoterapia [TÉCNICAS Y EQUIPOS ANALÍTICOS DIAGNÓSTICOS Y TERAPÉUTICOS] Carcinoembryonic Antigen Neoplasms [DISEASES] CP Antigen Càncer - Immunoteràpia Interferon-gamma patient-derived xenografts Immunotherapy células::células sanguíneas::leucocitos::leucocitos mononucleares::linfocitos::linfocitos T [ANATOMÍA] |
| Zdroj: | Scientia |
| ISSN: | 2211-1247 |
| Popis: | Cancer; Antigen; Resistance Cáncer; Antígeno; Resistencia Càncer; Antigen; Resistència Despite the revolution of immunotherapy in cancer treatment, patients eventually progress due to the emergence of resistance. In this scenario, the selection of the tumor antigen can be decisive in the success of the clinical response. T cell bispecific antibodies (TCBs) are engineered molecules that include binding sites to the T cell receptor and to a tumor antigen. Using gastric CEA+/HER2+ MKN45 cells and TCBs directed against CEA or HER2, we show that the mechanism of resistance to a TCB is dependent on the tumor antigen. Acquired resistant models to a high-affinity-CEA-targeted TCB exhibit a reduction of CEA levels due to transcriptional silencing, which is reversible upon 5-AZA treatment. In contrast, a HER2-TCB resistant model maintains HER2 levels and exhibit a disruption of the interferon-gamma signaling. These results will help in the design of combinatorial strategies to increase the efficacy of cancer immunotherapies and to anticipate and overcome resistances. This work was supported by Asociación Española Contra el Cancer (AECC), Breast Cancer Research Foundation (BCRF-21-008), and Instituto de Salud Carlos III (PI19/01181). A.M.S. was funded by the Spanish Government (PFIS FI20/00188). B.M. was funded by a fellowship from PERIS (Departament de Salut, Generalitat de Catalunya). M.R.A. was funded by Agency for Management of University and Research Grants (AGAUR, 2022 FI_B2 00080). P.O.R. was funded by the BBVA. E.J.A. was funded by the AECC (POSTD211413AREN). VHIO acknowledges the Cellex Foundation for providing research facilities and equipment, the Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) from the Institute of Health Carlos III (ISCIII), and the Department of Health (Generalitat de Catalunya, SLT008/18/00198 SLT008/18/00205) for their support on this research. The authors acknowledge financial support from the State Agency for Research (Agencia Estatal de Investigación) (CEX2020-001024-S/AEI/10.13039/501100011033) and for the Cancer Immunology and Immunotherapy (CAIMI-2) program funded by BBVA Foundation. We would like to remark the funding from B.M PERIS (Spain). The authors thank Dr. Anne Freimoser-Grundschober and Roche for helping provide the TCBs. The graphical abstract was created with BioRender.com. |
| Databáze: | OpenAIRE |
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