Priming of Colorectal Tumor-Associated Fibroblasts with Zoledronic Acid Conjugated to the Anti-Epidermal Growth Factor Receptor Antibody Cetuximab Elicits Anti-Tumor Vδ2 T Lymphocytes.
Priming of Colorectal Tumor-Associated Fibroblasts with Zoledronic Acid Conjugated to the Anti-Epidermal Growth Factor Receptor Antibody Cetuximab Elicits Anti-Tumor Vδ2 T Lymphocytes.
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肿瘤微环境中存在的不同细胞可以深刻影响包括结直肠癌（CRC）在内的实体肿瘤的癌症扩散和治疗成功。特别是，肿瘤相关成纤维细胞（TAF）发挥强大的免疫抑制作用，导致抗肿瘤监视功能受损，并干扰治疗抗体的功能。在这里，我们发现crc衍生的TAF可以被唑来膦酸（ZA）转化为可溶性形式或抗体-药物偶联物（ADC），成为抗肿瘤淋巴细胞的有效刺激物。ADC由用于结直肠癌治疗的抗egfr西妥昔单抗（Cet）和ZA （Cet-ZA）组成，可以诱导淋巴细胞增殖，从而杀死肿瘤细胞和TAF。双重结果是直接的抗癌作用和中和其基质的抑制活性。Cet-ZA ADC制剂的主要优点是除了CRC细胞外，还可以将ZA精确递送到EGFR+细胞，靶向TAF（潜在的免疫抑制）。肿瘤相关成纤维细胞（TAF）在结直肠癌（CRC）中发挥免疫抑制作用，损害包括Vδ2 T细胞在内的效应淋巴细胞对肿瘤细胞的识别。在这里，我们发现crc衍生的TAF可以被唑来膦酸（ZA）转化为可溶性形式或抗体-药物偶联物（ADC），成为Vδ2 T细胞的有效刺激物。CRC-TAF来源于患者，表达表皮生长因子受体（EGFR）和嗜丁酸蛋白家族成员BTN3A1/BTN2A1。这些嗜丁酸蛋白介导由于ZA效应在细胞中积累的磷酸抗原向Vδ2 T细胞的呈递。暴露于可溶性ZA的CRC-TAF获得了触发Vδ2 T细胞增殖的能力，部分表现为缺乏CD45RA和CD27的效应记忆细胞。反过来，扩增的Vδ2 T细胞对CRC细胞和CRC- taf发挥了相关的细胞毒活性。值得注意的是，我们最近描述的由抗egfr西妥昔单抗（Cet）和ZA （Cet-ZA）制成的ADC诱导了抗肿瘤Vδ2 T淋巴细胞的增殖及其对CRC-TAF的激活。这些结果表明，ZA可以诱导TAF刺激效应记忆Vδ2 T细胞；Cet-ZA ADC配方可将ZA精确递送至EGFR+细胞，同时双重靶向TAF和肿瘤细胞。
Different cells present in the tumor microenvironment can deeply influence both cancer spreading and the success of therapy in solid tumors, including colorectal carcinoma (CRC). In particular, tumor-associated fibroblasts (TAF) exert potent immunosuppressive effects leading to the impairment of anti-tumor surveillance and interfering with the function of therapeutic antibodies. Herein, we show that CRC-derived TAF can be turned by zoledronic acid (ZA), in soluble form or as antibody-drug conjugate (ADC), into efficient stimulators of anti-tumor lymphocytes. The ADC, made of the anti-EGFR cetuximab (Cet), used in CRC therapy, and ZA (Cet-ZA) can induce the proliferation of lymphocytes that become able to kill both tumor cells and TAF. The double result is a direct anti-cancer effect and the neutralization of the inhibitory activity exerted by its stroma. The major advantage of the Cet-ZA ADC formulation is the precise delivery of ZA to EGFR+ cells, targeting TAF (potentially immunosuppressive), besides CRC cells. Tumor-associated fibroblasts (TAF) exert immunosuppressive effects in colorectal carcinoma (CRC), impairing the recognition of tumor cells by effector lymphocytes, including Vδ2 T cells. Herein, we show that CRC-derived TAF can be turned by zoledronic acid (ZA), in soluble form or as antibody-drug conjugate (ADC), into efficient stimulators of Vδ2 T cells. CRC-TAF, obtained from patients, express the epidermal growth factor receptor (EGFR) and the butyrophilin family members BTN3A1/BTN2A1. These butyrophilins mediate the presentation of the phosphoantigens, accumulated in the cells due to ZA effect, to Vδ2 T cells. CRC-TAF exposed to soluble ZA acquired the ability to trigger the proliferation of Vδ2 T cells, in part represented by effector memory cells lacking CD45RA and CD27. In turn, expanded Vδ2 T cells exerted relevant cytotoxic activity towards CRC cells and CRC-TAF when primed with soluble ZA. Of note, also the ADC made of the anti-EGFR cetuximab (Cet) and ZA (Cet-ZA), that we recently described, induced the proliferation of anti-tumor Vδ2 T lymphocytes and their activation against CRC-TAF. These findings indicate that ZA can educate TAF to stimulate effector memory Vδ2 T cells; the Cet-ZA ADC formulation can lead to the precise delivery of ZA to EGFR+ cells, with a double targeting of TAF and tumor cells.
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影响因子：
5.2
作者：
Alfano M;Locatelli I;D'Arrigo C;Mora M;Vozzi G;De Acutis A;Pece R;Tavella S;Costa D;Poggi A;Zocchi MR
通讯作者：
Zocchi MR
影响因子：
10.9
作者：
通讯作者：
--
影响因子：
7.3
作者：
Costa D;Venè R;Benelli R;Romairone E;Scabini S;Catellani S;Rebesco B;Mastracci L;Grillo F;Minghelli S;Loiacono F;Zocchi MR;Poggi A
通讯作者：
Poggi A
影响因子：
20.3
作者：
Angelini, DF;Borsellino, G;Battistini, L
通讯作者：
Battistini, L
影响因子：
4.4
作者：
Corvaisier, M;Moreau-Aubry, A;Jotereau, F
通讯作者：
Jotereau, F