Tumor progression is independent of tumor-associated macrophages in cell lineage-based mouse models of glioblastoma.
Tumor progression is independent of tumor-associated macrophages in cell lineage-based mouse models of glioblastoma.
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DOI：
10.1073/pnas.2222084120
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发表时间：
2023-04-18
影响因子：
11.1
通讯作者：
Parada LF
中科院分区：
文献类型：
--
作者：
Chipman ME;Wang Z;Sun D;Pedraza AM;Bale TA;Parada LF
进一步了解胶质母细胞瘤（GBM）肿瘤免疫微环境以完善免疫策略是至关重要的。在这里，我们表明GBM肿瘤细胞谱系关联可以影响肿瘤免疫微环境中肿瘤相关巨噬细胞（TAMs）的丰度和个体发育。尽管免疫微环境组成不同，但TAM耗竭在所有测试模型中均未导致生存期延长。虽然TAM耗竭不延长生存，我们表明，脑室下区神经干细胞相关的GBM（1型）和少突胶质细胞祖细胞谱系相关的GBM（2型）有独特的转录响应TAM耗竭。我们强调，虽然TAM提供了重要的肿瘤支持信号，但一些GBM并不依赖于它们的生存。巨噬细胞靶向治疗在胶质母细胞瘤（GBM）中的临床成功有限。进一步了解GBM免疫微环境对于完善免疫学方法至关重要。在这里，我们使用基因工程小鼠模型和基于原位移植的GBM模型，具有相同的驱动突变和独特的起源细胞，以检查肿瘤细胞谱系在塑造免疫微环境和对肿瘤相关巨噬细胞（TAM）耗竭治疗的反应中的作用。我们发现，少突胶质细胞祖细胞谱系相关的GBM（2型）招募更多的免疫浸润，特别是单核细胞衍生的巨噬细胞比室管膜下区神经干细胞相关的GBM（1型）。然后，我们设计了一个TAM消耗系统，提供了一个独特的强大的和持续的TAM消耗。我们发现，在这些基于细胞系的GBM模型中，广泛的TAM消耗没有提供生存益处。尽管缺乏TAM消耗的生存益处，我们表明1型和2型GBM对TAM消耗具有独特的分子反应。总之，我们证明GBM细胞谱系影响TAM个体发育和丰度以及对TAM消耗的分子反应。
Further understanding the glioblastoma (GBM) tumor immune microenvironment to refine immunotherapeutic strategies is essential. Here, we show that GBM tumor cell lineage association can influence the abundance and ontogeny of tumor-associated macrophages (TAMs) in the tumor immune microenvironment. Despite differential immune microenvironment composition, TAM depletion results in no survival extension in all models tested. Although TAM depletion does not extend survival, we show that subventricular zone neural stem cell-associated GBMs (Type 1) and oligodendrocyte progenitor cell lineage-associated GBMs (Type 2) have unique transcriptional responses to TAM depletion. We highlight that although TAMs provide important tumor-supportive signals, some GBMs do not depend on them for survival. Macrophage targeting therapies have had limited clinical success in glioblastoma (GBM). Further understanding the GBM immune microenvironment is critical for refining immunotherapeutic approaches. Here, we use genetically engineered mouse models and orthotopic transplantation-based GBM models with identical driver mutations and unique cells of origin to examine the role of tumor cell lineage in shaping the immune microenvironment and response to tumor-associated macrophage (TAM) depletion therapy. We show that oligodendrocyte progenitor cell lineage-associated GBMs (Type 2) recruit more immune infiltrates and specifically monocyte-derived macrophages than subventricular zone neural stem cell-associated GBMs (Type 1). We then devise a TAM depletion system that offers a uniquely robust and sustained TAM depletion. We find that extensive TAM depletion in these cell lineage–based GBM models affords no survival benefit. Despite the lack of survival benefit of TAM depletion, we show that Type 1 and Type 2 GBMs have unique molecular responses to TAM depletion. In sum, we demonstrate that GBM cell lineage influences TAM ontogeny and abundance and molecular response to TAM depletion.
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影响因子：
16.6
作者：
Jiang N;Xie B;Xiao W;Fan M;Xu S;Duan Y;Hamsafar Y;Evans AC;Huang J;Zhou W;Lin X;Ye N;Wanggou S;Chen W;Jing D;Fragoso RC;Dugger BN;Wilson PF;Coleman MA;Xia S;Li X;Sun LQ;Monjazeb AM;Wang A;Murphy WJ;Kung HJ;Lam KS;Chen HW;Li JJ
通讯作者：
Li JJ
影响因子：
32.4
作者：
Hammond, Timothy R.;Dufort, Connor;Stevens, Beth
通讯作者：
Stevens, Beth
影响因子：
48
作者：
Buch, T;Heppner, FL;Waisman, A
通讯作者：
Waisman, A
DOI：
10.1038/s41573-022-00520-5
发表时间：
2022-11
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Klemm F;Maas RR;Bowman RL;Kornete M;Soukup K;Nassiri S;Brouland JP;Iacobuzio-Donahue CA;Brennan C;Tabar V;Gutin PH;Daniel RT;Hegi ME;Joyce JA
通讯作者：
Joyce JA