Zarodniuk Maksym, Steele Alexander, Lu Xin, Li Jun, Datta Meenal
Department of Aerospace and Mechanical Engineering, University of Notre Dame.
Department of Electrical Engineering, University of Notre Dame.
Res Sq. 2023 May 15:rs.3.rs-2931886. doi: 10.21203/rs.3.rs-2931886/v1.
Excessive deposition of extracellular matrix (ECM) is a hallmark of solid tumors; however, it remains poorly understood which cellular and molecular components contribute to the formation of ECM stroma in central nervous system (CNS) tumors. Here, we undertook a pan-CNS analysis of retrospective gene expression datasets to characterize inter- and intra-tumoral heterogeneity of ECM remodeling signatures in both adult and pediatric CNS disease. We found that CNS lesions - glioblastoma in particular - can be divided into two ECM-based subtypes (ECM and ECM) that are influenced by the presence of perivascular cells resembling cancer-associated fibroblasts (CAFs). We show that perivascular fibroblasts activate chemoattractant signaling pathways to recruit tumor-associated macrophages, and promote an immune-evasive, stem-like cancer cell phenotype. Our analysis reveals that perivascular fibroblasts are correlated with unfavorable response to immune checkpoint blockade in glioblastoma and poor patient survival across a subset of CNS tumors. We provide insights into novel stroma-driven mechanisms underlying immune evasion and immunotherapy resistance in CNS tumors like glioblastoma, and discuss how targeting these perivascular fibroblasts may prove an effective approach to improving treatment response and patient survival in a variety of CNS tumors.
细胞外基质（ECM）的过度沉积是实体瘤的一个标志；然而，对于中枢神经系统（CNS）肿瘤中哪些细胞和分子成分促成了ECM基质的形成，我们仍知之甚少。在此，我们对回顾性基因表达数据集进行了全中枢神经系统分析，以表征成人和儿童中枢神经系统疾病中ECM重塑特征的肿瘤间和肿瘤内异质性。我们发现中枢神经系统病变——尤其是胶质母细胞瘤——可分为两种基于ECM的亚型（ECM和ECM），它们受类似于癌症相关成纤维细胞（CAFs）的血管周围细胞的影响。我们表明，血管周围成纤维细胞激活趋化因子信号通路以招募肿瘤相关巨噬细胞，并促进一种免疫逃避、干细胞样癌细胞表型。我们的分析揭示，血管周围成纤维细胞与胶质母细胞瘤中对免疫检查点阻断的不良反应以及一部分中枢神经系统肿瘤患者的不良生存相关。我们深入了解了胶质母细胞瘤等中枢神经系统肿瘤中免疫逃避和免疫治疗耐药的新型基质驱动机制，并讨论了靶向这些血管周围成纤维细胞如何可能被证明是改善各种中枢神经系统肿瘤治疗反应和患者生存的有效方法。
