PO.IM01.10 · 免疫学
PD-1阻断与DLL3靶向T细胞衔接器联合可增强小细胞肺癌的抗肿瘤疗效
Combining PD-1 blockade with DLL3-targeted T cell engager potentiates antitumor efficacy in small cell lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
小细胞肺癌（SCLC）是一种侵袭性神经内分泌恶性肿瘤，其特征为快速增殖、早期转移和预后不良。尽管对化疗和免疫检查点阻断具有初始敏感性，大多数患者仍会经历疾病复发，这凸显了对新型治疗策略的迫切需求。Delta样配体3（DLL3）在SCLC细胞表面高表达，而在正常组织中极少表达，使其成为T细胞衔接疗法的理想靶点。然而，免疫浸润有限和免疫抑制性肿瘤微环境常限制了TCE在SCLC中的疗效。鉴于TCE（T细胞衔接器）介导的细胞毒性与PD-1阻断诱导的T细胞活化具有互补机制，我们的研究发现，将DLL3靶向TCE与PD-1抑制联合可显著增强抗肿瘤免疫反应并改善SCLC的治疗结果。在荷有SHP77（DLL3高表达）或NCI-H69（DLL3低表达）异种移植瘤的PBMC人源化小鼠模型中，DLL3 TCE联合pembrolizumab较DLL3 TCE单药取得了显著的抗肿瘤疗效。为阐明其潜在机制，我们发现联合治疗后肿瘤中人CD45+免疫细胞浸润显著增加。在仅用DLL3 TCE治疗的肿瘤中，肿瘤浸润T细胞上的PD-1表达上调，提示T细胞活化伴随抑制性免疫调节。值得注意的是，与pembrolizumab共同给药后PD-1表达降低，表明PD-1阻断有效逆转了免疫抑制性微环境并增强了免疫介导的肿瘤清除。此外，联合治疗不仅促进了T细胞的启动和活化，还增强了肿瘤微环境内癌细胞与T细胞之间的识别，提示形成了一种更具炎症性、免疫活跃的表型。该策略为DLL3靶向TCE与免疫检查点抑制剂联合用于SCLC治疗的临床评估提供了强有力的临床前依据。
查看英文原文 English abstract
Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid proliferation, early metastasis, and poor prognosis. Despite initial sensitivity to chemotherapy and immune checkpoint blockade, most patients experience disease relapse, highlighting the urgent need for novel therapeutic strategies. Delta-like ligand 3 (DLL3) is highly expressed on the surface of SCLC cells but minimally on normal tissues, making it an ideal target for T-cell-engaging therapies. However, limited immune infiltration and the immunosuppressive tumor microenvironment often restrict the efficacy of TCEs in SCLC. Given the complementary mechanism of TCE (T cell engager) mediated cytotoxicity and PD-1 blockade-induced T-cell activation, our research found that combining a DLL3-targeted TCE with PD-1 inhibition could enhance antitumor immune responses significantly and improve therapeutic outcomes in SCLC. In PBMC-humanized mouse models bearing SHP77 (DLL3-high expression) or NCI-H69 (DLL3-low expression) xenografts, DLL3 TCE combined with pembrolizumab achieved significant antitumor efficacy than DLL3 TCE monotherapy. To elucidate the underlying mechanisms, we found a marked increase infiltration of human CD45 + immune cells in tumors after combination treatment. In tumors treated with DLL3 TCE alone, PD-1 expression on tumor-infiltrated T cells was upregulated, suggesting T-cell activation accompanied by the inhibitory immune regulation. Notably, PD-1 expression decreased upon co-administration with pembrolizumab, indicating that PD-1 blockade effectively reversed immunosuppressive microenvironment and enhanced immune-mediated tumor clearance. Furthermore, the combination treatment not only promoted T-cell priming and activation but also enhanced recognition between cancer cells and T cells within the tumor microenvironment, indicating a more inflamed immunologically active phenotype. This strategy provides a strong preclinical rationale for clinical evaluation of DLL3-targeted TCEs in combination with immune checkpoint inhibitors for the treatment of SCLC.
利益披露 Disclosure
T. Huo, None..
T. Ni, None..
J. Wang, None..
P. Wang, None..
Y. Han, None..
Y. Zhang, None..
J. Xiang, None..
Z. Zhang, None.