Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital Bonn, Bonn, Germany.
Department of Neurosurgery, University Hospital Bonn, Bonn, Germany.
Front Immunol. 2022 Aug 25;13:925633. doi: 10.3389/fimmu.2022.925633. eCollection 2022.
Cytokine-induced killer cells (CIK) in combination with dendritic cells (DCs) have shown favorable outcomes in renal cell carcinoma (RCC), yet some patients exhibit recurrence or no response to this therapy. In a broader perspective, enhancing the antitumor response of DC-CIK cells may help to address this issue. Considering this, herein, we investigated the effect of anti-CD40 and anti-CTLA-4 antibodies on the antitumor response of DC-CIK cells against RCC cell lines. Our analysis showed that, a) anti-CD40 antibody (G28.5) increased the CD3+CD56+ effector cells of CIK cells by promoting the maturation and activation of DCs, b) G28.5 also increased CTLA-4 expression in CIK cells DCs, but the increase could be hindered by the CTLA-4 inhibitor (ipilimumab), c) adding ipilimumab was also able to significantly increase the proportion of CD3+CD56+ cells in DC-CIK cells, d) anti-CD40 antibodies predominated over anti-CTLA-4 antibodies for cytotoxicity, apoptotic effect and IFN-γ secretion of DC-CIK cells against RCC cells, e) after ipilimumab treatment, the population of Tregs in CIK cells remained unaffected, but ipilimumab combined with G28.5 significantly reduced the expression of CD28 in CIK cells. Taken together, we suggest that the agonistic anti-CD40 antibody rather than CTLA-4 inhibitor may improve the antitumor response of DC-CIK cells, particularly in RCC. In addition, we pointed towards the yet to be known contribution of CD28 in the crosstalk between anti-CTLA-4 and CIK cells.
细胞因子诱导的杀伤细胞（CIK）与树突状细胞（DC）联合应用于肾细胞癌（RCC）显示出良好的效果，但有些患者对这种治疗方法表现出复发或无反应。从更广泛的角度来看，增强 DC-CIK 细胞的抗肿瘤反应可能有助于解决这个问题。考虑到这一点，在这里，我们研究了抗 CD40 和抗 CTLA-4 抗体对 DC-CIK 细胞针对 RCC 细胞系的抗肿瘤反应的影响。我们的分析表明，a）抗 CD40 抗体（G28.5）通过促进 DC 的成熟和激活增加了 CIK 细胞的 CD3+CD56+效应细胞，b）G28.5 还增加了 CIK 细胞中 CTLA-4 的表达，但 CTLA-4 抑制剂（ipilimumab）可以阻止这种增加，c）添加 ipilimumab 也能够显著增加 DC-CIK 细胞中 CD3+CD56+细胞的比例，d）抗 CD40 抗体在细胞毒性、凋亡作用和 IFN-γ分泌方面优于抗 CTLA-4 抗体，对 DC-CIK 细胞针对 RCC 细胞，e）在 ipilimumab 治疗后，CIK 细胞中的 Tregs 群体不受影响，但 ipilimumab 联合 G28.5 显著降低了 CIK 细胞中 CD28 的表达。综上所述，我们认为激动性抗 CD40 抗体而不是 CTLA-4 抑制剂可能改善 DC-CIK 细胞的抗肿瘤反应，特别是在 RCC 中。此外，我们指出了 CD28 在抗 CTLA-4 与 CIK 细胞相互作用中的未知贡献。
