PO.CL05.06 · 临床研究

细胞毒性T细胞特征是高分化胃肠道神经内分泌肿瘤对177Lu-DOTATATE联合pembrolizumab治疗反应的基础

Cytotoxic T-cell signatures underlie therapeutic response to 177Lu-DOTATATE plus pembrolizumab in well-differentiated gastroenteric neuroendocrine tumors

编号 6455 展板 3 时间 4/21 02:00–05:00 区域 Section 41 主讲 Naoki Mizutani

分会场 Clinical Correlates of Immunotherapy

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作者与单位 Authors & Affiliations

Naoki Mizutani¹, Shloka Shukla¹, Nicholas Fidelman², Bridget P. Keenan², David Y. Oh², Kira Chan², Li Zhang², Emily K. Bergsland², Thomas Hope², Lawrence Fong¹

¹Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA,²University of California San Francisco, San Francisco, CA

摘要 Abstract

中文摘要

背景采用177Lu-DOTATATE的肽受体放射性核素治疗(PRRT)是高分化神经内分泌肿瘤(WD-NET)的一种成熟治疗方法。采用pembrolizumab的PD-1阻断已在NET中进行了研究；然而，作为单药治疗时影像学缓解有限。因此，我们研究了PRRT与pembrolizumab的联合应用作为一种增强抗肿瘤免疫和疗效的探索性方法，纳入26例2级或3级WD-NET患者(NCT03457948)。根据RECIST 1.1标准，总缓解率(ORR)为34.6%(9/26)，但该联合方案诱导的全身免疫变化仍未完全阐明。我们现报告使用PBMC的单细胞(sc)转录组学和TCR库分析对外周免疫重塑和T细胞克隆动力学的研究结果。方法从26例接受PRRT联合pembrolizumab治疗的患者中纵向收集了共111份PBMC样本。使用10x Genomics平台进行scRNA测序和TCR测序。对主要免疫细胞群进行注释，并分析其转录和克隆特征与治疗反应的关系。患者分为胰腺NET(pNET，N=14；5例缓解者[36%，PR]和9例非缓解者[64%；7例SD，2例PD])和胰腺外NET(epNET，N=12；4例缓解者[33%，PR]和8例非缓解者[67%；7例SD，1例PD])，后者包括肠道、肺部及原发灶不明来源的肿瘤。统计分析采用Mann-Whitney U检验。结果在epNET缓解者中，与epNET非缓解者相比，CD8⁺ T细胞的频率在各时间点均升高(p<0.05)。对T细胞进一步亚聚类显示，CD4⁺和一个CD8⁺细胞毒性T细胞亚群在epNET缓解者中均显著升高(p<0.05)，并表现出显著的克隆扩增，尤其是在治疗后。非缓解者表现出免疫抑制性亚群的富集，包括CD4⁺调节性T细胞(Treg)和CD4⁺ Th2细胞(p<0.05)。差异基因表达分析表明，与非缓解者相比，缓解者的CD4⁺和CD8⁺ T细胞中若干细胞毒性基因(NKG7、CCL5、GNLY和GZMH)上调。与epNET不同，无论反应状态如何，pNET患者的全身免疫重塑总体上有限。结论综合单细胞和TCR分析揭示了对PRRT联合PD-1阻断的缓解者与非缓解者之间存在不同的全身T细胞活化特征，但这种效应因原发部位而异。epNET的缓解患者表现出显著的克隆扩增和细胞毒性基因上调。这些发现突出了WD-NET中与治疗反应相关的外周免疫动力学的关键差异，可能为优化联合治疗策略提供参考。

查看英文原文 English abstract

Background Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE is an established treatment for well-differentiated neuroendocrine tumors (WD-NETs). PD-1 blockade with pembrolizumab has been investigated in NETs; however, radiographic responses are limited when used as monotherapy. As such, we investigated the combination of PRRT and pembrolizumab as an investigational approach to enhance antitumor immunity and efficacy in 26 patients with grade 2 or 3 WD-NET (NCT03457948). The overall response rate (ORR) by RECIST 1.1 was 34.6% (9/26), but the systemic immune changes induced by this combination remain incompletely understood. We now report the results of our investigation of peripheral immune remodeling and T-cell clonal dynamics using single-cell (sc) transcriptomic and TCR repertoire profiling of PBMCs. Methods A total of 111 PBMC samples were collected longitudinally from 26 patients treated with PRRT plus pembrolizumab. scRNA sequencing and TCR sequencing were performed using the 10x Genomics platform. Major immune populations were annotated, and transcriptional and clonal characteristics were analyzed in relation to treatment response. Patients were stratified into pancreatic NET (pNET, N=14; 5 responders [36%, PR] and 9 non-responders [64%; 7 SD, 2 PD]) and extrapancreatic NET (epNET, N=12; 4 responders [33%, PR] and 8 non-responders [67%; 7 SD, 1 PD]), with the latter including tumors of intestinal, pulmonary, and unknown primary origin. Statistical analysis was performed with Mann-Whitney U test. Results In epNET responders, the frequency of CD8⁺ T cells increased across timepoints compared with epNET non-responders (p<0.05). Further subclustering of T cells revealed that both CD4⁺ and a subset of CD8⁺ cytotoxic T cells were significantly elevated (p<0.05) and exhibited prominent clonal expansion in epNET responders, particularly post treatment. Non-responders showed an enrichment of immunosuppressive subsets, including CD4⁺ regulatory T cells (Treg) and CD4⁺ Th2 cells (p<0.05). Differential gene expression analysis demonstrated that several cytotoxic genes ( N KG7 , CCL5 , GNLY , and GZMH ) were upregulated in both CD4⁺ and CD8⁺ T cells in the responders compared with non-responders. In contrast to epNET, systemic immune remodeling was generally limited in pNET patients regardless of response status. Conclusions Integrated single-cell and TCR analysis revealed distinct systemic T-cell activation profiles between responders and non-responders to PRRT plus PD-1 blockade, but this effect varied by site of origin. Responding patients with epNET exhibited prominent clonal expansion and upregulation of cytotoxic genes. These findings highlight key differences in peripheral immune dynamics associated with treatment response in WD-NETs and may inform strategies to optimize combination therapy.

利益披露 Disclosure

N. Mizutani, Daiichi Sankyo Co., Lts Employment. S. Shukla, None. N. Fidelman, Merck & Co., Inc. ). B. P. Keenan, AstraZeneca ). Roche/Genentech ). Regeneron ). Takeda ). Antengene ). Innovative Cellular Therapeutics ). Affini-T ). Pyxis Oncology ). Arcellx Independent Contractor. Agenus Inc. Independent Contractor. Cartography Biosciences Independent Contractor. Roche/Genentech Travel. D. Y. Oh, Merck ). PACT Pharma ). the Parker Institute for Cancer Immunotherapy ). Poseida Therapeutics ). TCR2 Therapeutics ). Roche/Genentech ). Nutcracker Therapeutics ). Amgen ). Allogene Therapeutics ). Roche/Genentech Travel. Poseida Therapeutics Travel. DAVA Oncology Travel. Tatum Bioscience g., Board of Directors, non-salaried role). Cartography Biosciences g., Board of Directors, non-salaried role). Revelation Partners Independent Contractor. K. Chan, None. L. Zhang, Motive Medical Intelligence Independent Contractor. Smith-Kettlewell Eye Research Institute Independent Contractor. Serna Bio Independent Contractor. E. K. Bergsland, Merck & Co., Inc. ). T. Hope, Bayer ). GE Healthcare ). Lantheus ). Janssen ). Novartis ). Telix Pharmaceuticals ). the Prostate Cancer Foundation ). National Cancer Institute ). AstraZeneca Independent Contractor. Bayer Independent Contractor. Cardinal Health Independent Contractor. BlueEarth Diagnostics Independent Contractor. Lantheus Independent Contractor. Molecular Partners Independent Contractor. Novartis Independent Contractor. RayzeBio/BMS Independent Contractor. Sanofi Independent Contractor. Curium Stock. AdvanCell Stock. Utter Therapeutics Stock. L. Fong, Merck & Co., Inc. g., Board of Directors, non-salaried role), ). Roche/Genentech g., Board of Directors, non-salaried role), ). Actym g., Board of Directors, non-salaried role). Astra Zeneca g., Board of Directors, non-salaried role). Bioatla g., Board of Directors, non-salaried role). Boehringer Ingelheim g., Board of Directors, non-salaried role). Daiichi Sankyo g., Board of Directors, non-salaried role). Immunogenesis g., Board of Directors, non-salaried role). Innovent g., Board of Directors, non-salaried role). Merck KGA g., Board of Directors, non-salaried role). Nutcracker g., Board of Directors, non-salaried role). Sutro g., Board of Directors, non-salaried role).

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