肿瘤细胞治疗研究
英文原题：Itolizumab regulates activating and inhibitory signals on effector cells, improving their cytotoxicity against CD318+ tumor cell lines.
CD6-CD318轴已成为免疫肿瘤学的潜在靶点。近期研究表明，使用鼠抗人CD6抗体阻断CD6-CD318相互作用可增强淋巴细胞细胞毒性。然而，多项研究已证实鼠源抗体临床应用的弊端以及抗CD6抗体之间的变异性。因此，first-in-class人源化抗人CD6抗体itolizumab可用于癌症免疫治疗的证据，可能成为开发抗肿瘤临床方法的突破。
CD6-CD318轴已成为免疫肿瘤学的潜在靶点。近期研究表明，使用鼠抗人CD6抗体阻断CD6-CD318相互作用可增强淋巴细胞细胞毒性。然而，多项研究已证实鼠源抗体临床应用的弊端以及抗CD6抗体之间的变异性。因此，first-in-class人源化抗人CD6抗体itolizumab可用于癌症免疫治疗的证据，可能成为开发抗肿瘤临床方法的突破。
通过流式细胞术对健康供者外周血单个核细胞（PBMCs）在CD318+细胞系刺激后的表型和功能特征进行了分析。此外，通过ELISA检测培养上清中的IFNγ。还对乳腺肿瘤样本进行了免疫组化分析。结果与讨论：在此，我们提供了支持itolizumab用于癌症免疫治疗合理性的证据。itolizumab阻断CD6-CD318相互作用可增强CD8 T细胞和NK细胞对CD318+肿瘤细胞系的细胞毒性能力，逆转NKG2A/NKG2D比值，并增加颗粒酶B和IFNγ的产生。itolizumab还通过下调淋巴细胞上CD5表达以及上调PD-1和CTLA-4抑制性受体来调节免疫应答，这有助于减轻过度加剧的应答，并在与其他免疫检查点抑制剂联合时叠加增强对CD318+肿瘤细胞的细胞毒性。此外，我们报道CD6-CD318相互作用在体外和人类乳腺癌组织样本中抑制淋巴细胞增殖和存活，同时下调淋巴细胞上的CD6表达，这强化了CD6-CD318轴作为免疫检查点的作用，并突出了itolizumab作为免疫检查点抑制剂的潜力。综上所述，我们的结果首次提供了将itolizumab阻断CD6-CD318轴与增强淋巴细胞功能特性联系起来的证据，突出itolizumab作为一种针对CD318+肿瘤的新型有前景的免疫疗法，并支持其与检查点抑制剂联合治疗的相关性。
INTRODUCTION: The CD6-CD318 axis has emerged as a potential target for immuno-oncology. Recent work has shown that blocking the CD6-CD318 interaction with a murine anti-human CD6 antibody increases lymphocyte cytotoxicity. However, several studies have demonstrated the drawbacks associated with the clinical use of murine antibodies and the variability among anti-CD6 antibodies. Therefore, evidence that the first-in-class humanized anti-human CD6 antibody itolizumab could be used for cancer immunotherapy may be a breakthrough in developing an antitumor clinical approach. METHODS: Phenotypic and functional characterization of peripheral blood mononuclear cells (PBMCs) from healthy donors after challenge with CD318+ cell lines was performed by flow cytometry. In addition, IFNγ was determined by ELISA in culture supernatants. Immunohistochemical analyses of breast tumor samples were also performed. RESULTS AND DISCUSSION: Here, we provide evidence supporting the rationale for itolizumab in cancer immunotherapy. The blockade of the CD6-CD318 interaction by itolizumab increases the cytotoxic capacity of CD8 T and NK cells over CD318+ tumor lines, reverses the NKG2A/NKG2D ratio, and increases granzyme B and IFNγ production. Itolizumab also regulates immune responses by downregulating CD5 expression and upregulating PD-1 and CTLA-4 inhibitory receptors on lymphocytes, which contribute to reducing exacerbated responses and additively enhancing CD318+ tumor cell cytotoxicity when combined with other immunocheckpoint inhibitors. In addition, we report that CD6-CD318 interaction inhibits lymphocyte proliferation and survival while downregulating CD6 expression on lymphocytes in vitro and in human breast cancer tissue samples, reinforcing the role of the CD6-CD318 axis as an immune checkpoint and highlighting the potential of itolizumab as an immune checkpoint inhibitor. Taken together, our results provide the first evidence linking the blocking of the CD6-CD318 axis by itolizumab with the potentiation of functional properties of lymphocytes, highlighting itolizumab as a novel promising immunotherapy for CD318+ tumors and supporting the relevance of new combinatorial therapies with checkpoint inhibitors.
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