Dynamics of tertiary lymphoid structures and immune cross talk in early versus advanced colorectal cancer: potential implications for immunotherapy.

IF 4.6 2区医学 Q2 IMMUNOLOGY

Cancer Immunology, Immunotherapy Pub Date : 2025-04-26 DOI:10.1007/s00262-025-04027-x

Zixu Chen, Bang Hu, Keyu Cai, Han Gao, Zhenyu Xian, Shuang Zhang, Zhen Fang, Qian Zhou, Donglin Ren, Qi Zou

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Abstract

Background: Irrespective of microsatellite status, immune checkpoint inhibitor therapy shows superior efficacy in early-stage colorectal cancer (CRC) compared to advanced cases. The distinctions of the tumor microenvironment (TME) and tertiary lymphoid structure (TLS) between early- and advanced-stage CRC may represent a critical factor, yet remain incompletely elucidated.

Methods: We comprehensively analyzed single-cell RNA sequencing data, bulk RNA transcription data and pathological tissue data to investigate the dynamic changes in the TME. The features of TLS in early- and advanced-stage tumors and their potential impact on immunotherapy were explored using three in-house cohorts.

Results: We provided single-cell fine maps of the immune landscape in early and advanced CRC. Significant functional differences were identified in CD4 + Tfh and BGC cells between early and advanced CRC. We revealed CXCL13 expression on CD8 + Tex cells, along with CD40-CD40L interactions between CD4 + Tfh and BGC cells, could be key regulators of TLS functionality and subsequently affect the response to immunotherapy.

Conclusions: Our research shed light on the multilayered immune dysfunction in advanced CRC and elucidates the alterations in the TLS during the progression of CRC, providing insights for functional studies and the exploration of potential target in advanced CRC.

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早期和晚期结直肠癌的三级淋巴结构和免疫串扰动力学：免疫治疗的潜在意义。

背景：无论微卫星状态如何，免疫检查点抑制剂治疗在早期结直肠癌（CRC）中的疗效优于晚期病例。早期和晚期CRC之间肿瘤微环境（TME）和三级淋巴结构（TLS）的差异可能是一个关键因素，但尚未完全阐明。方法：综合分析单细胞RNA测序数据、大量RNA转录数据和病理组织数据，探讨TME的动态变化。通过三个内部队列，探讨了TLS在早期和晚期肿瘤中的特征及其对免疫治疗的潜在影响。结果：我们提供了早期和晚期结直肠癌免疫景观的单细胞精细图谱。早期和晚期结直肠癌患者CD4 + Tfh和BGC细胞功能差异显著。我们发现CXCL13在CD8 + Tex细胞上的表达，以及CD4 + Tfh和BGC细胞之间CD40-CD40L的相互作用可能是TLS功能的关键调节因子，并随后影响对免疫治疗的反应。结论：我们的研究揭示了晚期结直肠癌的多层免疫功能障碍，阐明了TLS在结直肠癌进展过程中的改变，为晚期结直肠癌的功能研究和潜在靶点的探索提供了新的思路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Immunology, Immunotherapy 医学-免疫学

CiteScore

10.50

自引率

1.70%

发文量

207

审稿时长

1 months

期刊介绍： Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions. The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.