Kundu Somanath, Mitra Soham, Roshini Arivazhagan, Longo John A, Longo Sharon L, Venskus Abigail G, Babu Harish, Viapiano Mariano S
Department of Neuroscience and Physiology, State University of New York - Upstate Medical University, Syracuse, New York.
Department of Neurosurgery, State University of New York - Upstate Medical University, Syracuse, New York.
Cancer Res Commun. 2025 Sep 1;5(9):1599-1610. doi: 10.1158/2767-9764.CRC-25-0083.
Glioblastoma (GBM) tumors remain a challenge for immunotherapy owing to their heterogeneous and immunologically cold properties. GBM cells change the composition of the neural extracellular matrix (ECM), affecting the mobility, survival, and function of immune cells such as tumor-associated microglia and infiltrated macrophages (TAM). The ECM protein fibulin-3/EFEMP1 is a pericellular component uniquely upregulated in GBM compared with the normal brain, which promotes tumor growth and invasion. In this study, we demonstrate that fibulin-3 indirectly modulates TAM behavior and can be targeted to restore innate immune responses. Intracranial tumors initiated by fibulin-3-deficient GBM cells showed increased presence of TAMs with decreased immunosuppression markers (arginase-1, CD206), whereas the opposite effects were observed in tumors overexpressing fibulin-3. In silico analyses revealed a positive correlation between fibulin-3 and an immunosuppressive signature that was validated in GBM stem cells and in vivo. We further demonstrated that fibulin-3 regulates the expression of immunosuppressive signals (CSF-1, TGF-β1, and CD47) by autocrine activation of NF-κB signaling. Immunosuppressive signals were downregulated by knockdown of fibulin-3 in GBM stem cells and by inhibition of this protein using an anti-fibulin-3 antibody. Myeloid cells exhibited higher phagocytic activity and killing of GBM cells in presence of this antibody. Furthermore, locoregional delivery of anti-fibulin-3 in mice with intracranial GBM increased the presence of proinflammatory TAMs, thereby reducing tumor viability. Our findings show that anti-fibulin-3 approaches, which affect the ECM surrounding tumor and immune cells, can diminish immunosuppression in GBM and boost innate immune responses against the tumor.
Inhibition of the ECM protein fibulin-3, which is highly upregulated in glioblastoma tumors, decreases immunosuppressive signals produced by the tumor cells and exposes them to increased attack by TAMs.
胶质母细胞瘤（GBM）肿瘤由于其异质性和免疫冷特性，仍然是免疫治疗的一个挑战。GBM细胞改变神经细胞外基质（ECM）的组成，影响肿瘤相关小胶质细胞和浸润巨噬细胞（TAM）等免疫细胞的迁移、存活和功能。ECM蛋白纤维连接蛋白-3/EFEMP1是一种细胞周围成分，与正常脑相比，在GBM中独特地上调，它促进肿瘤生长和侵袭。在本研究中，我们证明纤维连接蛋白-3间接调节TAM行为，并且可以靶向恢复先天免疫反应。由纤维连接蛋白-3缺陷的GBM细胞引发的颅内肿瘤显示TAM的存在增加，免疫抑制标志物（精氨酸酶-1、CD206）减少，而在过表达纤维连接蛋白-3的肿瘤中观察到相反的效果。计算机分析显示纤维连接蛋白-3与免疫抑制特征之间呈正相关，这在GBM干细胞和体内得到验证。我们进一步证明纤维连接蛋白-3通过NF-κB信号的自分泌激活来调节免疫抑制信号（CSF-1、TGF-β1和CD47）的表达。通过在GBM干细胞中敲低纤维连接蛋白-3以及使用抗纤维连接蛋白-3抗体抑制该蛋白，免疫抑制信号被下调。在存在这种抗体的情况下，髓样细胞表现出更高的吞噬活性和对GBM细胞的杀伤作用。此外，在颅内GBM小鼠中局部递送抗纤维连接蛋白-3增加了促炎性TAM的存在，从而降低了肿瘤活力。我们的研究结果表明，影响肿瘤和免疫细胞周围ECM的抗纤维连接蛋白-3方法可以减少GBM中的免疫抑制，并增强针对肿瘤的先天免疫反应。
抑制在胶质母细胞瘤肿瘤中高度上调的ECM蛋白纤维连接蛋白-3，可减少肿瘤细胞产生的免疫抑制信号，并使它们更容易受到TAM的攻击。
