Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
J Immunother Cancer. 2022 Jul;10(7). doi: 10.1136/jitc-2022-005063.
There was much hard work to study the trastuzumab resistance in HER2-positive gastric cancer (GC), but the information which would reveal this abstruse mechanism is little. In this study, we aimed to investigate the roles of tumor cell-derived CCL2 on trastuzumab resistance and overcome the resistance by treatment with the anti-CD40-scFv-linked anti-HER2 (CD40 ×HER2) bispecific antibody (bsAb).
We measured the levels of CCL2 expression in HER2-positive GC tissues, and revealed biological functions of tumor cell-derived CCL2 on tumor-associated macrophages (TAMs) and the trastuzumab resistance. Then, we developed CD40 ×HER2 bsAb, and examined the targeting roles on HER2 and CD40, to overcome the trastuzumab resistance without systemic toxicity.
We found the level of CCL2 expression in HER2-postive GC was correlated with infiltration of TAMs, polarization status of infiltrated TAMs, trastuzumab resistance and survival outcomes of GC patients. On exposure to CCL2, TAMs decreased the M1-like phenotype, thereby eliciting the trastuzumab resistance. CCL2 activated the transcription of ZC3H12A, which increased K63-linked deubiquitination and K48-linked auto-ubiquitination of TRAF6/3 to inactivate NF-κB signaling in TAMs. CD40 ×HER2 bsAb, which targeted the CD40 to restore the ubiquitination level of TRAF6/3, increased the M1-like phenotypic transformation of TAMs, and overcame trastuzumab resistance without immune-related adversary effects (irAEs).
We revealed a novel mechanism of trastuzumab resistance in HER2-positive GC via the CCL2-ZC3H12A-TRAF6/3 signaling axis, and presented a CD40 ×HER2 bsAb which showed great antitumor efficacy with few irAEs.
在研究 HER2 阳性胃癌（GC）的曲妥珠单抗耐药方面做了很多艰苦的工作，但揭示这一深奥机制的信息却很少。在这项研究中，我们旨在探讨肿瘤细胞衍生的 CCL2 对曲妥珠单抗耐药的作用，并通过使用抗-CD40-scFv 连接的抗-HER2（CD40×HER2）双特异性抗体（bsAb）来克服耐药性。
我们测量了 HER2 阳性 GC 组织中 CCL2 的表达水平，揭示了肿瘤细胞衍生的 CCL2 对肿瘤相关巨噬细胞（TAMs）和曲妥珠单抗耐药的生物学功能。然后，我们开发了 CD40×HER2 bsAb，并研究了其对 HER2 和 CD40 的靶向作用，以克服曲妥珠单抗耐药而无全身毒性。
我们发现 HER2 阳性 GC 中 CCL2 的表达水平与 TAMs 的浸润、浸润 TAMs 的极化状态、曲妥珠单抗耐药和 GC 患者的生存结果相关。在 CCL2 暴露下，TAMs 减少了 M1 样表型，从而引发了曲妥珠单抗耐药。CCL2 激活了 ZC3H12A 的转录，从而增加了 TRAF6/3 的 K63 连接去泛素化和 K48 连接自泛素化，使 TAMs 中的 NF-κB 信号失活。靶向 CD40 以恢复 TRAF6/3 的泛素化水平的 CD40×HER2 bsAb，增加了 TAMs 的 M1 样表型转化，克服了曲妥珠单抗耐药，而没有免疫相关不良反应（irAEs）。
我们通过 CCL2-ZC3H12A-TRAF6/3 信号轴揭示了 HER2 阳性 GC 中曲妥珠单抗耐药的新机制，并提出了一种 CD40×HER2 bsAb，该抗体具有很少的 irAEs，但具有强大的抗肿瘤疗效。
