CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Identification of Pancreatic Ductal Adenocarcinoma Extracellular Matrix Signatures from In-Depth Proteomic Profiling that Correlate with Lymphocyte Infiltration.
Identification of Pancreatic Ductal Adenocarcinoma Extracellular Matrix Signatures from In-Depth Proteomic Profiling that Correlate with Lymphocyte Infiltration.
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细胞外基质（ECM）是围绕细胞的复杂蛋白质组装体。它是肿瘤微环境（TME）的关键组成部分，在肿瘤进展和调节肿瘤对治疗的反应中发挥积极作用。胰腺导管腺癌（PDAC）是一种以预后最差为特征的癌症类型，因为它通常在晚期才被诊断出来。它还具有非常致密的ECM，这阻碍了有效的药物递送。此外，PDAC被认为是“冷”肿瘤，因为它们无法引发强烈的免疫反应，这对PDAC患者的免疫治疗应用构成了挑战。然而，PDAC TME中ECM与免疫细胞之间的相互作用仍知之甚少。在本研究中，我们使用以ECM为重点的蛋白质组学来分析具有不同水平CD8+ T细胞浸润的PDAC小鼠模型的ECM组成。我们发现CD8lo或“冷”肿瘤与CD8hi或“热”肿瘤表现出不同的ECM谱。对公开可用的人类PDAC单细胞RNA测序数据集的进一步分析揭示，区分热和冷PDAC的ECM蛋白由多种基质细胞群体分泌，包括癌症相关成纤维细胞、星状细胞和巨噬细胞。最后，我们发现，在人类PDAC样本中，一组编码CD8lo表型特征性ECM蛋白的基因的表达与CD8+ T细胞浸润和患者生存相关。本研究为开发调节ECM的干预措施以增强免疫细胞浸润和对免疫治疗的反应性铺平了道路。意义：我们报道了在小鼠PDAC模型和人类样本中，与CD8+淋巴细胞浸润水平相关的ECM蛋白特征的鉴定。这项工作为开发ECM调节治疗策略铺平了道路，以增强淋巴细胞浸润，从而提高免疫疗法的疗效。
UNLABELLED: The extracellular matrix (ECM) is a complex assembly of proteins surrounding cells. It is a critical component of the tumor microenvironment (TME) that plays an active role in tumor progression and modulation of tumor response to treatment. Pancreatic ductal adenocarcinoma (PDAC) is a cancer type characterized by one of the worst prognoses, as it is often diagnosed at an advanced stage. It is also characterized by a very dense ECM, which hinders efficient drug delivery.
In addition, PDACs are considered "cold" tumors as they fail to elicit a strong immune response, challenging the use of immunotherapy for patients with PDAC cancer. Yet, the interplay between the ECM and immune cells within the PDAC TME remains poorly understood. In this study, we used ECM-focused proteomics to profile the ECM compositions of PDAC mouse models characterized by different levels of CD8+ T-cell infiltration.
We found that CD8lo, or "cold" tumors, and CD8hi, or "hot" tumors, exhibited different ECM profiles. Interrogation of publicly available single-cell RNA sequencing datasets of human PDACs further revealed that the ECM proteins distinguishing hot and cold PDACs are secreted by multiple stromal cell populations, including cancer-associated fibroblasts, stellate cells, and macrophages.
Last, we found that the expression of a subset of the genes encoding ECM proteins characteristic of the CD8lo phenotype correlated with CD8+ T-cell infiltration in human PDAC samples and patient survival.
This study paves the way for the development of ECM-modulating interventions to enhance immune cell infiltration and responsiveness to immunotherapy. SIGNIFICANCE: We report the identification of ECM protein signatures correlating with the level of CD8+ lymphocyte infiltration in murine models of PDACs and human samples. This work paves the way for the development of ECM-modulating therapeutic strategies to enhance lymphocyte infiltration and, hence, the efficacy of immunotherapies.
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