肿瘤细胞治疗研究
英文原题：Spatial single-cell proteotyping reveals immunotherapy-resistant features within the complex tumor microenvironment of metastatic NSCLC.
背景：靶向程序性细胞死亡1轴的免疫检查点抑制剂（ICIs）已彻底改变了转移性非小细胞肺癌（mNSCLC）的治疗。
背景 靶向程序性细胞死亡1轴的免疫检查点抑制剂（ICI）已彻底改变了转移性非小细胞肺癌（mNSCLC）的治疗。然而，疾病进展仍是一个令人担忧的问题，复杂肿瘤微环境（TME）在治疗失败中的作用尚未完全阐明。 方法 在这项纳入103例mNSCLC患者（包括81例接受ICI治疗的患者）的生物标志物研究中，我们通过对治疗前肿瘤组织进行单细胞空间分析，使用专为深入剖析TME而构建的29标志物多重IHC平台，评估了异质性免疫细胞亚群与ICI疗效之间的关联。 结果 在包括Th1、Treg和NK细胞在内的多种瘤内淋巴细胞中，仅CD8+ T细胞（TIL（肿瘤浸润淋巴细胞）[TIL]）与ICI疗效相关。计算性组织分割强调了CD8+ TIL与癌细胞之间直接物理相互作用对ICI疗效的重要性。TIL表型分析确定CD39/CD103/Ki-67阳性是耗竭但具有功能的肿瘤反应性CD8+ TIL的标志。免疫抑制性肿瘤相关巨噬细胞（TAM）和癌相关成纤维细胞是独立的不良因素。癌细胞上高CD73表达被认为赋予EGFR/ALK驱动基因阳性NSCLC对ICI的耐受性，可能通过M2-TAM积聚和异常血管生成实现。 结论 我们的研究描绘了异质性免疫细胞亚群在ICI治疗的mNSCLC中的临床相关性，有助于靶向治疗策略的开发。 资助 大阪癌症学会、KANAE医学科学促进基金会、SGH基金会和YOKOYAMA临床药理学基金会。
BACKGROUNDImmune checkpoint inhibitors (ICIs) targeting the programmed cell death 1 axis have revolutionized metastatic non-small cell lung cancer (mNSCLC) treatment. However, disease progression remains a concern, and the role of the complex tumor microenvironment (TME) in treatment failure is not fully understood.METHODSIn this biomarker study involving 103 patients with mNSCLC, including 81 patients who received ICI treatment, we evaluated the association between heterogeneous immune cell subsets and ICI efficacy through single-cell spatial profiling of pretreatment tumor tissue, using a 29-marker multiplex IHC platform built for in-depth dissection of the TME.RESULTSAmong various types of intratumoral lymphocytes, including Th1, Treg, and NK cells, only CD8+ T cells (tumor-infiltrating lymphocytes [TILs]) were associated with ICI efficacy. Computational tissue segmentation underscored the importance of direct physical interactions between CD8+ TILs and cancer cells for ICI efficacy. TIL phenotyping identified CD39/CD103/Ki-67 positivity as a hallmark of exhausted yet functional tumor-reactive CD8+ TILs. Immunosuppressive tumor-associated macrophages (TAMs) and cancer-associated fibroblasts were independent unfavorable adversaries. High CD73 expression on cancer cells was suggested to confer tolerance to ICI in EGFR/ALK-oncogene+ NSCLC, potentially through M2-TAM accumulation and aberrant angiogenesis.CONCLUSIONOur study delineates the clinical relevance of heterogeneous immune cell subsets in ICI-treated mNSCLC, aiding the development of targeted therapeutic strategies.FUNDINGOsaka Cancer Society, KANAE Foundation for the Promotion of Medical Science, SGH Foundation, and YOKOYAMA Foundation for Clinical Pharmacology.
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