PO.CL05.06 · 临床研究

非小细胞肺癌中与免疫检查点抑制剂长期反应和耐药相关的免疫学和转录特征

Immunologic and transcriptional features associated with long-term response and resistance to immune checkpoint inhibitors in non-small cell lung cancer checkpoint inhibitors in non-small cell lung cancer

编号 6460 展板 8 时间 4/21 02:00–05:00 区域 Section 41 主讲 YOSHIHIRO MASUI, MD

分会场 Clinical Correlates of Immunotherapy

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作者与单位 Authors & Affiliations

Yoshihiro Masui¹, Tatsuya Yoshida¹, Jun Miyakoshi¹, Ryoko Higashiyama¹, Akiko Tateishi¹, Yuki Shinno¹, Tomonori Mizutani¹, Yusuke Okuma¹, Hidehito Horinouchi¹, Kouya Shiraishi², Takashi Kohno², Yasushi Goto¹

¹Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan,²Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan

摘要 Abstract

中文摘要

背景：免疫检查点抑制剂(ICI)显著改善了非小细胞肺癌(NSCLC)的结局，但仅有少数患者获得持久获益。肿瘤对ICI反应的生物学机制——包括原发耐药(PriR)、获得性耐药(AcqR)和长期反应(LTR)——仍知之甚少。方法：我们回顾了2015-2020年间在日本国立癌症中心医院开始一线ICI单药治疗的晚期或复发性NSCLC患者。患者分为LTR(定义为无进展生存期≥48个月)、AcqR(初始疾病控制后进展<48个月)或PriR(最佳反应为PD)。对这些组的临床特征进行了描述。对治疗前肿瘤RNA-seq数据进行转录组学分析。使用Hallmark和Reactome GSEA评估差异通路活性，并使用CIBERSORT推断免疫细胞组成。结果：临床队列共纳入216例患者。46例患者具有治疗前肿瘤RNA-seq数据(LTR，n=10；AcqR，n=23；PriR，n=13)。与缓解者(LTR+AcqR)相比，PriR肿瘤显示出炎症和免疫抑制程序的显著富集，包括IL6-JAK-STAT3、TNFalpha/NF-κB、补体、糖酵解和缺氧通路，提示存在一种阻碍初始免疫激活的代谢应激和抑制性微环境。相比之下，缓解者表现出更高的干扰素-gamma(IFN-gamma)信号传导和T细胞活化特征。在LTR和AcqR的直接比较中，LTR肿瘤独特地保留了强烈的IFN-gamma驱动的炎症、完整的MHC I类抗原呈递机制以及稳健的细胞毒性和记忆T细胞程序。AcqR肿瘤显示抗原呈递和效应免疫通路减弱，提示免疫原性降低促成了初始反应后的进展。在PD-L1高表达肿瘤中，LTR病例同样维持了完整的抗原呈递机制和持续的IFN-gamma驱动的细胞毒性T细胞活性，而AcqR肿瘤表现出这些程序的减弱。结论：与PriR和AcqR肿瘤相比，LTR肿瘤显示出更高的IFN-gamma活性、保留的抗原呈递活性和持续的效应T细胞信号传导。PriR肿瘤的特征是炎症和代谢应激的免疫抑制程序，而AcqR肿瘤在初始反应后显示抗原呈递和效应免疫活性的丧失。这些特征可能有助于识别可能获得持久ICI获益的患者，并提示克服耐药的潜在靶点。

查看英文原文 English abstract

Background: Immune checkpoint inhibitors (ICIs) have markedly improved outcomes in non-small cell lung cancer (NSCLC), yet durable benefit is achieved in only a minority of patients. The biological mechanisms underlying tumor response to ICIs-including primary resistance (PriR), acquired resistance (AcqR), and long-term response (LTR)-remain poorly understood. Methods: We reviewed patients with advanced or recurrent NSCLC who initiated first-line ICI monotherapy at the National Cancer Center Hospital (Japan) between 2015-2020. Patients were classified as LTR (defined as progression-free survival ≥48 months), AcqR (initial disease control followed by progression <48 months), or PriR (best response PD). Clinical characteristics were characterized across these groups. Pretreatment tumor RNA-seq data were subjected to transcriptomic analyses. Differential pathway activity was evaluated using Hallmark and Reactome GSEA, and immune-cell composition was inferred using CIBERSORT. Results: A total of 216 patients were included in the clinical cohort. Pretreatment tumor RNA-seq data were available for 46 patients (LTR, n=10; AcqR, n=23; PriR, n=13). Compared with responders (LTR + AcqR), PriR tumors showed marked enrichment of inflammatory and immunosuppressive programs, including IL6-JAK-STAT3, TNFalpha/NF-κB, complement, glycolysis, and hypoxia pathways, suggesting a metabolically stressed and suppressive microenvironment that hinders initial immune activation. In contrast, responders exhibited higher interferon-gamma (IFN-gamma) signaling and T-cell activation signatures. In a direct comparison between LTR and AcqR, LTR tumors uniquely preserved strong IFN-gamma-driven inflammation, intact MHC class I antigen-presentation machinery, and robust cytotoxic and memory T-cell programs. AcqR tumors showed attenuation of antigen-presentation and effector-immune pathways, suggesting that reduced immunogenicity contributes to progression after an initial response. Among PD-L1-high tumors, LTR cases again maintained intact antigen-presentation machinery and sustained IFN-gamma-driven cytotoxic T-cell activity, whereas AcqR tumors demonstrated attenuation of these programs. Conclusion: Compared with PriR and AcqR tumors, LTR tumors showed higher IFN-gamma activity, preserved antigen-presentation activity, and sustained effector T-cell signaling. PriR tumors were characterized by inflammatory and metabolically stressed immunosuppressive programs, whereas AcqR tumors showed loss of antigen-presentation and effector-immune activity after the initial response. These features may help identify patients likely to achieve durable ICI benefit and suggest potential targets to overcome resistance.

利益披露 Disclosure

Y. Masui, None. T. Yoshida, Pfizer Inc. Other, Honorarium. Chugai Pharmaceutical Co., Ltd. Other, Honorarium. Daiichi Sankyo Co., Ltd. ), Other, Honorarium. AstraZeneca K.K. ), Other, Honorarium. MSD K.K. ), Other, Honorarium. Novartis Pharma K.K. ). Eli Lilly Japan K.K. ). Bristol-Myers Squibb K.K. ). Astellas Pharma Inc. ). Amgen K.K. ). Boehringer Ingelheim Japan, Inc. ). J. Miyakoshi, None.. R. Higashiyama, None.. A. Tateishi, None. Y. Shinno, Ono Pharmaceutical Co., Ltd. ). Janssen Pharmaceutical K.K. ). Taiho Pharmaceutical Co., Ltd. ). Bayer Yakuhin, Ltd. ). AstraZeneca K.K. ). Daiichi Sankyo Co., Ltd. ). T. Mizutani, None. Y. Okuma, AstraZeneca K.K. ). Chugai Pharmaceutical Co., Ltd. Other, Honorarium. Eli Lilly Japan K.K. Other, Honorarium. MSD K.K. ). H. Horinouchi, AstraZeneca K.K. ), Other, Honorarium. Novartis Pharma K.K. ). MSD K.K. ). Bristol-Myers Squibb K.K. ). Daiichi Sankyo Co., Ltd. ). AbbVie GK ). IQVIA Services Japan K.K. ). Astellas Amgen Biopharma K.K. ). Ono Pharmaceutical Co., Ltd. ). Takeda Pharmaceutical Company Limited ). Janssen Pharmaceutical K.K. ). Amgen K.K. Other, Honorarium. Chugai Pharmaceutical Co., Ltd. Other, Honorarium. K. Shiraishi, None.. T. Kohno, None. Y. Goto, Novartis Pharma K.K. ). MSD K.K. ). Daiichi Sankyo Co., Ltd. ), Other, Honorarium. IQVIA Services Japan K.K. ). Chugai Pharmaceutical Co., Ltd. ), Other, Honorarium. EPS Corporation ). AstraZeneca K.K. ), Other, Honorarium. Pfizer Japan Inc. ). Eli Lilly Japan K.K. ). Chugai Pharmaceutical Co., Ltd. ).

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