In vitro elimination of epidermal growth factor receptor-overexpressing cancer cells by CD32A-chimeric receptor T cells in combination with cetuximab or panitumumab.
In vitro elimination of epidermal growth factor receptor-overexpressing cancer cells by CD32A-chimeric receptor T cells in combination with cetuximab or panitumumab.
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DOI：
10.1002/ijc.32663
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发表时间：
2020-01-01
影响因子：
6.4
通讯作者：
Sconocchia G
中科院分区：
文献类型：
--
作者：
Caratelli S;Arriga R;Sconocchia T;Ottaviani A;Lanzilli G;Pastore D;Cenciarelli C;Venditti A;Del Principe MI;Lauro D;Landoni E;Du H;Savoldo B;Ferrone S;Dotti G;Sconocchia G
西妥昔单抗和帕尼单抗结合人表皮生长因子受体（EGFR）。虽然嵌合西妥昔单抗（IgG1）会触发EGFR阳性靶细胞的抗体依赖性细胞毒性（ADCC），但帕尼单抗（人IgG2）不会。panitumumab无法触发ADCC反映了人IgG2 Fc对自然杀伤（NK）细胞的Fcγ riii （CD16）的结合亲和力较差。然而，人IgG1和IgG2结合FcγRII （CD32A）的程度相似。我们的研究比较了用一种新型低亲和力cd32a131r -嵌合受体（CR）改造的T细胞和那些用低亲和力CD16158F-CR T细胞改造的T细胞在联合西妥昔单抗或帕尼单抗的情况下消除EGFR阳性上皮癌细胞（ECCs）的能力。T细胞转导后，CD32A131R-CR T细胞比例为74±10%，CD16158F-CR T细胞比例为46±15%。只有CD32A131R-CR T细胞结合帕尼单抗。CD32A131R-CR T细胞与mAb 8.26（抗cd32）联合，CD16158F-CR T细胞与mAb 3g8（抗cd16）联合，在体外逆转ADCC实验中消除结直肠癌（CRC）， HCT116FcγR+细胞。用西妥昔单抗或帕尼单抗交联CD32A131R-CR T细胞和用西妥昔单抗交联CD16158F-CR T细胞可诱导三阴性乳腺癌（TNBC） MDA-MB-468细胞的消除，并分泌干扰素γ和肿瘤坏死因子α。西妥昔单抗和帕尼单抗均未诱导Fcγ-CR T抗Kirsten大鼠肉瘤（KRAS）突变的HCT116、非小细胞肺癌、A549和TNBC、MDA-MB-231细胞的抗肿瘤活性。Fcγ-CR T细胞的ADCC与EGFR在ECCs上的过表达有关。总之，CD32A131R-CR T细胞可以通过西妥昔单抗或帕尼单抗有效地靶向过表达EGFR的乳腺癌细胞。
Cetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). Although the chimeric cetuximab (IgG1) triggers antibody-dependent-cellular-cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects the poor binding affinity of human IgG2 Fc for the FcγRIII (CD16) on natural killer (NK) cells. However, both human IgG1 and IgG2 bind the FcγRII (CD32A) to a similar extent. Our study compares the ability of T cells, engineered with a novel low-affinity CD32A131R-chimeric receptor (CR), and those engineered with the low-affinity CD16158F-CR T cells, in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. After T-cell transduction, the percentage of CD32A131R-CR T cells was 74 ± 10%, whereas the percentage of CD16158F-CR T cells was 46 ± 15%. Only CD32A131R-CR T cells bound panitumumab. CD32A131R-CR T cells combined with the mAb 8.26 (anti-CD32) and CD16158F-CR T cells combined with the mAb 3g8 (anti-CD16) eliminated colorectal carcinoma (CRC), HCT116FcγR+ cells, in a reverse ADCC assay in vitro. Crosslinking of CD32A131R-CR on T cells by cetuximab or panitumumab and CD16158F-CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA-MB-468 cells, and the secretion of interferon gamma and tumor necrosis factor alpha. Neither cetuximab nor panitumumab induced Fcγ-CR T antitumor activity against Kirsten rat sarcoma (KRAS)-mutated HCT116, nonsmall-cell-lung-cancer, A549 and TNBC, MDA-MB-231 cells. The ADCC of Fcγ-CR T cells was associated with the overexpression of EGFR on ECCs. In conclusion, CD32A131R-CR T cells are efficiently redirected by cetuximab or panitumumab against breast cancer cells overexpressing EGFR.
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