Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.
Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, Republic of Korea.
J Immunother Cancer. 2020 Aug;8(2). doi: 10.1136/jitc-2020-000873.
BACKGROUND: Although programmed cell death-1/programmed death-ligand 1 (PD-L1) inhibitors show remarkable antitumor activity, a large portion of patients with cancer, even those with high PD-L1-expressing tumors, do not respond to their effects. Most PD-L1 inhibitors contain modified fragment crystallizable region (Fc) receptor binding sites to prevent antibody-dependent cellular cytotoxicity (ADCC) against PD-L1-expressing non-tumor cells. However, natural killer (NK) cells have specific antitumor activity in the presence of tumor-targeting antibody through ADCC, which could enhance NK cell-induced cytotoxicity. We evaluated the antitumor efficacy of ADCC via anti-PD-L1 monoclonal antibodies (mAbs) and NK cells against several PD-L1-positive cancer cell lines. METHODS: Various cancer cell lines were used as target cell lines. Surface PD-L1 expression was analyzed by flow cytometry. IMC-001 and anti-hPD-L1-hIgG1 were tested as anti-PD-L1 mAbs with ADCC and atezolizumab as an anti-PD-L1 mAb without ADCC. NK cell cytotoxicity was measured by Cr-release assay and CD107a degranulation assay. Also, live cell imaging was performed to evaluate cytotoxicity in a single-cell level. NK-92-CD16 (CD16-transduced NK-92 cell line) and peripheral blood mononuclear cells from healthy donors, respectively, were used as an effector cell. FcγRIIIa (CD16a)-V158F genotyping was performed for healthy donors. RESULTS: We demonstrated that the cytotoxicity of NK-92-CD16 cells toward PD-L1-positive cancer cell lines was significantly enhanced in the presence of anti-PD-L1 mAb with ADCC. We also noted a significant increase in primary human NK cell cytotoxicity against PD-L1-positive human cancer cells when cocultured with anti-PD-L1 mAb with ADCC. Moreover, NK cells expressing a high-affinity genotype displayed higher anti-PD-L1 mAb-mediated ADCC lysis of tumor cells than donors with a low-affinity genotype. CONCLUSION: These results suggest that NK cells induce an ADCC response in combination with anti-PD-L1 mAbs, which helps promote ADCC antitumor activity against PD-L1-positive tumors. This study provides support for NK cell immunotherapy against high PD-L1-expressing tumors in combination with ADCC through anti-PD-L1 mAbs.
背景：尽管程序性细胞死亡-1/程序性死亡配体 1（PD-L1）抑制剂显示出显著的抗肿瘤活性，但仍有很大一部分癌症患者，甚至是那些 PD-L1 高表达肿瘤患者，对其治疗效果没有反应。大多数 PD-L1 抑制剂含有经过修饰的片段结晶区（Fc）受体结合位点，以防止针对 PD-L1 表达的非肿瘤细胞的抗体依赖性细胞毒性（ADCC）。然而，自然杀伤（NK）细胞在存在肿瘤靶向抗体的情况下通过 ADCC 具有特异性抗肿瘤活性，这可以增强 NK 细胞诱导的细胞毒性。我们评估了通过抗 PD-L1 单克隆抗体（mAb）和 NK 细胞针对几种 PD-L1 阳性癌细胞系的 ADCC 的抗肿瘤疗效。
方法：将各种癌细胞系用作靶细胞系。通过流式细胞术分析表面 PD-L1 表达。我们测试了 IMC-001 和抗-hPD-L1-hIgG1 作为具有 ADCC 的抗 PD-L1 mAb，以及作为不具有 ADCC 的抗 PD-L1 mAb 的 atezolizumab。通过 Cr 释放测定和 CD107a 脱颗粒测定来测量 NK 细胞的细胞毒性。此外，还进行了活细胞成像以评估单细胞水平的细胞毒性。分别使用 NK-92-CD16（转导了 CD16 的 NK-92 细胞系）和来自健康供体的外周血单核细胞作为效应细胞。对健康供体进行了 FcγRIIIa（CD16a）-V158F 基因分型。
结果：我们证明，当存在具有 ADCC 的抗 PD-L1 mAb 时，NK-92-CD16 细胞对 PD-L1 阳性癌细胞系的细胞毒性显著增强。我们还注意到，当与具有 ADCC 的抗 PD-L1 mAb 共培养时，原代人 NK 细胞对 PD-L1 阳性人癌细胞的细胞毒性显著增加。此外，表达高亲和力基因型的 NK 细胞对肿瘤细胞的抗 PD-L1 mAb 介导的 ADCC 裂解作用高于具有低亲和力基因型的供体。
结论：这些结果表明，NK 细胞与抗 PD-L1 mAb 一起诱导 ADCC 反应，这有助于促进针对 PD-L1 阳性肿瘤的 ADCC 抗肿瘤活性。这项研究为 NK 细胞免疫疗法提供了支持，该疗法通过抗 PD-L1 mAb 与 ADCC 结合，用于治疗高 PD-L1 表达的肿瘤。
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