CD16-158-valine chimeric receptor T cells overcome the resistance of KRAS-mutated colorectal carcinoma cells to cetuximab.
CD16-158-valine chimeric receptor T cells overcome the resistance of KRAS-mutated colorectal carcinoma cells to cetuximab.
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DOI：
10.1002/ijc.32618
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发表时间：
2020-05-01
影响因子：
6.4
通讯作者：
Sconocchia G
中科院分区：
文献类型：
--
作者：
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
KRAS突变阻碍表皮生长因子受体（EGFR）特异性单克隆抗体西妥昔单抗和帕尼单抗为基础的EGFR+癌症免疫治疗的疗效。尽管西妥昔单抗通过自然杀伤（NK）细胞介导的抗体依赖性细胞毒性（ADCC）在体外抑制KRAS突变的癌细胞生长，但KRAS突变的结直肠癌（CRC）细胞在体内逃避NK细胞的免疫监视。为了克服这一限制，我们使用西妥昔单抗和帕尼单抗将Fcγ嵌合受体（CR）T细胞重定向至KRAS突变的HCT 116结直肠癌（CRC）细胞。我们比较了通过逆转录病毒载体转导到T细胞中的四种多态性Fcγ-CR构建体，包括CD 16158 F-CR、CD 16158 V-CR、CD 32131 H-CR和CD 32131 R-CR。表达CD 32131 H-CR和CD 32131 R-CR的T细胞的存活率分别为83.5 ± 9.5和77.7 ± 13.2，显著高于表达CD 16158 F-CR和CD 16158 V-CR的T细胞的存活率（分别为30.3 ± 10.2和51.7 ± 13.7）（p < 0.003）。CD 32131 R-CR T细胞特异性结合可溶性西妥昔单抗和帕尼单抗。然而，在与西妥昔单抗调理的HCT 116细胞一起孵育时，仅CD 16158 V-CR T细胞释放高水平的干扰素γ（IFNγ = 1，145.5 pg/ml ± 16.5 pg/ml，p <0.001）和肿瘤坏死因子α（TNFα = 614 pg/ml ± 21 pg/ml，p < 0.001）。此外，只有CD 16158 V-CR T细胞与西妥昔单抗组合在体外杀死HCT 116细胞和A549 KRAS突变细胞。CD 16158 V-CR T细胞还有效地控制了CB 17-SCID小鼠中HCT 116细胞的体内皮下生长。因此，CD 16158 V-CR T细胞与西妥昔单抗组合代表了开发创新的EGFR+ KRAS突变的CRC免疫疗法的有用试剂。
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.
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影响因子：
5.4
作者：
Cheeseman HM;Olejniczak NJ;Rogers PM;Evans AB;King DFL;Ziprin P;Liao HX;Haynes BF;Shattock RJ
通讯作者：
Shattock RJ
影响因子：
6.4
作者：
Sconocchia, Giuseppe;Zlobec, Inti;Lugli, Alessandro;Calabrese, Diego;Iezzi, Giandomenica;Karamitopoulou, Eva;Patsouris, Efstratios S.;Peros, George;Horcic, Milo;Tornillo, Luigi;Zuber, Markus;Droeser, Raoul;Muraro, Manuele G.;Mengus, Chantal;Oertli, Daniel;Ferrone, Soldano;Terracciano, Luigi;Spagnoli, Giulio C.
通讯作者：
Spagnoli, Giulio C.
影响因子：
3.9
作者：
Coppola A;Arriga R;Lauro D;Del Principe MI;Buccisano F;Maurillo L;Palomba P;Venditti A;Sconocchia G
通讯作者：
Sconocchia G
影响因子：
4.5
作者：
D'Aloia, Maria Michela;Caratelli, Sara;Alimandi, Maurizio
通讯作者：
Alimandi, Maurizio
影响因子：
15.9
作者：
SHAW, GM;LEVY, PC;LOBUGLIO, AF
通讯作者：
LOBUGLIO, AF