Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Cancer Immunol Immunother. 2023 May;72(5):1153-1167. doi: 10.1007/s00262-022-03317-y. Epub 2022 Nov 10.
Multiple myeloma (MM) is an incurable hematological cancer, in which immune checkpoint inhibition (ICI) with monoclonal antibodies (mAbs) has failed due to uncontrollable immune responses in combination therapies and lack of efficacy in monotherapies. Although NK cell-specific checkpoint targets such as NKG2A and KIRs are currently being evaluated in clinical trials, the clinical impact of NK cells on the PD1 cascade is less well understood compared to T cells. Furthermore, while NK cells have effector activity within the TME, under continuous ligand exposure, NK cell dysfunctionality may occur due to interaction of PD1 and its ligand PD-L1. Due to above-mentioned factors, we designed novel NK cell specific PD1-based chimeric switch receptors (PD1-CSR) by employing signaling domains of DAP10, DAP12 and CD3ζ to revert NK cell inhibition and retarget ICI. PD1-CSR modified NK cells showed increased degranulation, cytokine secretion and cytotoxicity upon recognition of PD-L1 target cells. Additionally, PD1-CSR NK cells infiltrated and killed tumor spheroids. While primary NK cells (pNK), expressing native PD1, showed decreased degranulation and cytokine production against PD-L1 target cells by twofold, PD1-CSR pNK cells demonstrated increased activity upon PD-L1 target cell recognition and enhanced antibody-dependent cellular cytotoxicity. PD1-CSR pNK cells from patients with MM increased degranulation and cytokine expression against autologous CD138PD-L1 malignant plasma cells. Taken together, the present results demonstrate that PD1-CSR NK cells enhance and sustain potent anti-tumor activity in a PD-L1 microenvironment and thus represent a promising strategy to advance adoptive NK cell-based immunotherapies toward PD-L1 cancers.
多发性骨髓瘤（MM）是一种无法治愈的血液系统癌症，由于联合治疗中不可控的免疫反应和单一疗法缺乏疗效，免疫检查点抑制（ICI）与单克隆抗体（mAbs）结合的治疗方法已经失败。尽管目前正在临床试验中评估 NK 细胞特异性检查点靶标，如 NKG2A 和 KIRs，但与 T 细胞相比，NK 细胞对 PD1 级联反应的临床影响了解得还不够充分。此外，虽然 NK 细胞在 TME 中具有效应活性，但在持续的配体暴露下，由于 PD1 与其配体 PD-L1 的相互作用，NK 细胞可能会出现功能障碍。由于上述因素，我们通过利用 DAP10、DAP12 和 CD3ζ 的信号结构域，设计了新型的基于 PD1 的 NK 细胞特异性嵌合开关受体（PD1-CSR），以逆转 NK 细胞抑制并重新靶向 ICI。在识别 PD-L1 靶细胞时，经 PD1-CSR 修饰的 NK 细胞显示出脱颗粒、细胞因子分泌和细胞毒性增加。此外，PD1-CSR NK 细胞能够渗透并杀伤肿瘤球体。虽然表达天然 PD1 的原代 NK 细胞（pNK）对 PD-L1 靶细胞的脱颗粒和细胞因子产生减少了两倍，但 PD1-CSR pNK 细胞在识别 PD-L1 靶细胞时表现出更高的活性，并增强了抗体依赖性细胞毒性。来自 MM 患者的 PD1-CSR pNK 细胞对自身 CD138PD-L1 恶性浆细胞的脱颗粒和细胞因子表达增加。总之，这些结果表明 PD1-CSR NK 细胞在 PD-L1 微环境中增强并维持强大的抗肿瘤活性，因此代表了一种有前途的策略，可以推进基于 NK 细胞的免疫疗法治疗 PD-L1 癌症。
