Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Arriga, R; Caratelli, S; Lanzilli, G; Ottaviani, A; Cenciarelli, C; Sconocchia, T; Spagnoli, GC; Iezzi, G; Roselli, M; Lauro, D; Coppola, A; Dotti, G; Ferrone, S; Sconocchia, G.
CD16-158-valine chimeric receptor T cells overcome the resistance of KRAS-mutated colorectal carcinoma cells to cetuximab.
Int J Cancer. 2020; 146(9):2531-2538
Doi: 10.1002/ijc.32618
[OPEN ACCESS]
Web of Science
PubMed
FullText
FullText_MUG
- Co-Autor*innen der Med Uni Graz
- Sconocchia Tommaso
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation analytics):
- Abstract:
- KRAS mutations hinder therapeutic efficacy of epidermal growth factor receptor (EGFR)-specific monoclonal antibodies cetuximab and panitumumab-based immunotherapy of EGFR+ cancers. Although cetuximab inhibits KRAS-mutated cancer cell growth in vitro by natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), KRAS-mutated colorectal carcinoma (CRC) cells escape NK cell immunosurveillance in vivo. To overcome this limitation, we used cetuximab and panitumumab to redirect Fcγ chimeric receptor (CR) T cells against KRAS-mutated HCT116 colorectal cancer (CRC) cells. We compared four polymorphic Fcγ-CR constructs including CD16158F -CR, CD16158V -CR, CD32131H -CR, and CD32131R -CR transduced into T cells by retroviral vectors. Percentages of transduced T cells expressing CD32131H -CR (83.5 ± 9.5) and CD32131R -CR (77.7 ± 13.2) were significantly higher than those expressing with CD16158F -CR (30.3 ± 10.2) and CD16158V -CR (51.7 ± 13.7) (p < 0.003). CD32131R -CR T cells specifically bound soluble cetuximab and panitumumab. However, only CD16158V -CR T cells released high levels of interferon gamma (IFNγ = 1,145.5 pg/ml ±16.5 pg/ml, p < 0.001) and tumor necrosis factor alpha (TNFα = 614 pg/ml ± 21 pg/ml, p < 0.001) upon incubation with cetuximab-opsonized HCT116 cells. Moreover, only CD16158V -CR T cells combined with cetuximab killed HCT116 cells and A549 KRAS-mutated cells in vitro. CD16158V -CR T cells also effectively controlled subcutaneous growth of HCT116 cells in CB17-SCID mice in vivo. Thus, CD16158V -CR T cells combined with cetuximab represent useful reagents to develop innovative EGFR+KRAS-mutated CRC immunotherapies.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals - administration & dosage
- Antineoplastic Agents, Immunological - pharmacology
- Apoptosis - administration & dosage
- Cell Proliferation - administration & dosage
- Cetuximab - pharmacology
- Colorectal Neoplasms - genetics, immunology, pathology, therapy
- Drug Resistance, Neoplasm - administration & dosage
- Humans - administration & dosage
- Immunotherapy, Adoptive - methods
- Male - administration & dosage
- Mice - administration & dosage
- Mice, SCID - administration & dosage
- Mutation - administration & dosage
- Proto-Oncogene Proteins p21(ras) - genetics
- Receptors, Antigen, T-Cell - immunology
- Receptors, IgG - genetics, immunology
- Tumor Cells, Cultured - administration & dosage
- Valine - genetics
- Xenograft Model Antitumor Assays - administration & dosage
- Find related publications in this database (Keywords)
- Fc gamma CR T cells
- polymorphisms
- immunotherapy
- KRAS-mutated CRC
- anti-EGFR mAb