小柯机器人

瑞典乌普萨拉大学Anna Dimberg研究组发现，通过AAV治疗调整血管表型可促进胶质瘤的抗肿瘤免疫。2023年5月11日出版的《癌细胞》杂志发表了这项成果。

他们使用脑内皮细胞靶向腺相关病毒(AAV)载体在胶质瘤脉管系统中表达LIGHT (AAV-LIGHT)。他们发现，系统性AAV-LIGHT治疗可诱导肿瘤相关的高内皮小静脉(HEVs)和富含T细胞的三级淋巴样结构(TLS)，延长αPD-1耐药小鼠胶质瘤的生存期。AAV-LIGHT治疗可减少T细胞衰竭，促进TCF1+CD8+干细胞样T细胞，这些细胞位于TLS和肿瘤内抗原呈递壁龛中。AAV-LIGHT治疗后肿瘤消退与肿瘤特异性细胞毒性/记忆T细胞反应相关。

他们的研究表明，通过血管靶向表达LIGHT来改变血管表型可以促进有效的抗肿瘤T细胞反应并延长胶质瘤的生存期。这些发现对其他免疫治疗耐药癌症的治疗具有更广泛的意义。

据了解，胶质母细胞瘤是侵袭性脑肿瘤，对免疫治疗有很大的抵抗力。这与免疫抑制和功能失调的肿瘤血管系统有关，这阻碍了T细胞的浸润。LIGHT/TNFSF14可诱导HEV和TLS，表明其治疗性表达可促进T细胞募集。

附：英文原文

Title: Tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma

Author: Mohanraj Ramachandran, Alessandra Vaccaro, Tiarne van de Walle, Maria Georganaki, Roberta Lugano, Kalyani Vemuri, Despoina Kourougkiaouri, Konstantinos Vazaios, Marie Hedlund, Georgia Tsaridou, Lene Uhrbom, Ilkka Pietil, Miika Martikainen, Luuk van Hooren, Thomas Olsson Bontell, Asgeir S. Jakola, Di Yu, Bengt Westermark, Magnus Essand, Anna Dimberg

Issue&Volume: 2023-05-11

Abstract: Glioblastomas are aggressive brain tumors that are largely immunotherapy resistant. This is associated with immunosuppression and a dysfunctional tumor vasculature, which hinder T cell infiltration. LIGHT/TNFSF14 can induce high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), suggesting that its therapeutic expression could promote T cell recruitment. Here, we use a brain endothelial cell-targeted adeno-associated viral (AAV) vector to express LIGHT in the glioma vasculature (AAV-LIGHT). We found that systemic AAV-LIGHT treatment induces tumor-associated HEVs and T cell-rich TLS, prolonging survival in αPD-1-resistant murine glioma. AAV-LIGHT treatment reduces T cell exhaustion and promotes TCF1+CD8+ stem-like T cells, which reside in TLS and intratumoral antigen-presenting niches. Tumor regression upon AAV-LIGHT therapy correlates with tumor-specific cytotoxic/memory T cell responses. Our work reveals that altering vascular phenotype through vessel-targeted expression of LIGHT promotes efficient anti-tumor T cell responses and prolongs survival in glioma. These findings have broader implications for treatment of other immunotherapy-resistant cancers.

DOI: 10.1016/j.ccell.2023.04.010

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00136-8

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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