CD16-158-Valine Chimeric Receptor T Cells Overcome the Resistance of KRAS-mutated Colorectal Carcinoma Cells to Cetuximab
ABSTRACT KRAS mutation hinders the therapeutic efficacy of epidermal-growth-factor-receptor (EGFR) mAb (cetuximab and panitumumab)-based immunotherapy of EGFR+ cancers. Although, cetuximab controls KRAS-mutated cancer cell growthin vitroutilizing a NK cell-mediated antibody-dependent-cellular-cytotoxicity-(ADCC) mechanism, KRAS-mutated colorectal carcinoma (CRC) cells can still escape NK cell immunosurveillance. To overcome this limitation, we used cetuximab and panitumumab to redirect Fcγ chimeric receptor (CR) T cells against KRAS-mutated HCT116 CRC cells. We compared 4 polymorphic Fcγ-CR constructs including CD16158F-CR, CD16158V-CR, CD32131H-CR, and CD32131R-CR which were transduced into T cells utilizing retroviral transduction. 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 significantly higher levels of interferon gamma (IFNγ=1145.5 pg/ml ±16.5 pg/ml, p<0.001) and tumor necrosis factor alpha (TNFα=614 pg/ml ± 21 pg/ml, p<0.001) than non-transduced T cells when incubated with KRAS-mutated HCT116 cells opsonized with cetuximab. Only CD16158V-CR T cells combined with cetuximab controlled the growth of HCT116 cells subcutaneously engrafted in CB17-SCID mice. These results suggest that CD16158V-CR T cells combined with cetuximab represent useful reagents to develop an effective immunotherapy of EGFR+KRAS-mutated cancer..
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Preprint| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
bioRxiv.org - (2020) vom: 04. Dez. Zur Gesamtaufnahme - year:2020 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Arriga, Roberto [VerfasserIn] |
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| Links: |
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| doi: |
10.1101/588525 |
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| PPN (Katalog-ID): |
XBI000481858 |
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| 520 | |a ABSTRACT KRAS mutation hinders the therapeutic efficacy of epidermal-growth-factor-receptor (EGFR) mAb (cetuximab and panitumumab)-based immunotherapy of EGFR+ cancers. Although, cetuximab controls KRAS-mutated cancer cell growthin vitroutilizing a NK cell-mediated antibody-dependent-cellular-cytotoxicity-(ADCC) mechanism, KRAS-mutated colorectal carcinoma (CRC) cells can still escape NK cell immunosurveillance. To overcome this limitation, we used cetuximab and panitumumab to redirect Fcγ chimeric receptor (CR) T cells against KRAS-mutated HCT116 CRC cells. We compared 4 polymorphic Fcγ-CR constructs including CD16158F-CR, CD16158V-CR, CD32131H-CR, and CD32131R-CR which were transduced into T cells utilizing retroviral transduction. 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 significantly higher levels of interferon gamma (IFNγ=1145.5 pg/ml ±16.5 pg/ml, p<0.001) and tumor necrosis factor alpha (TNFα=614 pg/ml ± 21 pg/ml, p<0.001) than non-transduced T cells when incubated with KRAS-mutated HCT116 cells opsonized with cetuximab. Only CD16158V-CR T cells combined with cetuximab controlled the growth of HCT116 cells subcutaneously engrafted in CB17-SCID mice. These results suggest that CD16158V-CR T cells combined with cetuximab represent useful reagents to develop an effective immunotherapy of EGFR+KRAS-mutated cancer. | ||
| 700 | 1 | |a Caratelli, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Lanzilli, Giulia |e verfasserin |4 aut | |
| 700 | 1 | |a Ottaviani, Alessio |e verfasserin |4 aut | |
| 700 | 1 | |a Cenciarelli, Carlo |e verfasserin |4 aut | |
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