肿瘤细胞治疗研究
英文原题：Cancer-associated MSC drive tumor immune exclusion and resistance to immunotherapy, which can be overcome by Hedgehog inhibition.
我们研究了癌症相关间充质干细胞（CA-MSCs）对卵巢肿瘤免疫的影响。
我们研究了癌症相关间充质干细胞（CA-MSCs）对卵巢肿瘤免疫的影响。在患者样本中，CA-MSC的存在与肿瘤内CD8+ T细胞的存在呈负相关。使用免疫热小鼠卵巢癌模型，我们发现CA-MSCs通过分泌多种趋化因子（Ccl2、Cx3cl1和Tgf-β1），驱动CD8+ T细胞肿瘤免疫排斥，并降低对抗PD-L1免疫检查点抑制剂（ICI）的反应，这些趋化因子招募免疫抑制性CD14+ Ly6C+ Cx3cr1+单核细胞，并将巨噬细胞极化为免疫抑制性Ccr2hi F4/80+ Cx3cr1+ CD206+表型。单核细胞和巨噬细胞均高表达转化生长因子诱导（Tgfbi）蛋白，该蛋白抑制NK细胞活性。Hedgehog抑制剂（HHi）治疗逆转了CA-MSC效应，减少髓系细胞的存在和Tgfbi的表达，增加肿瘤内NK细胞数量，并恢复对ICI治疗的反应。因此，CA-MSCs调节抗肿瘤免疫，CA-MSC hedgehog信号是癌症免疫治疗的重要靶点。
We investigated the impact of cancer-associated mesenchymal stem cells (CA-MSCs) on ovarian tumor immunity. In patient samples, CA-MSC presence inversely correlates with the presence of intratumoral CD8 + T cells. Using an immune hot mouse ovarian cancer model, we found that CA-MSCs drive CD8 + T cell tumor immune exclusion and reduce response to anti PD-L1 immune checkpoint inhibitor (ICI) via secretion of numerous chemokines (Ccl2, Cx3cl1, and Tgf- 1), which recruit immune-suppressive CD14 + Ly6C + Cx3cr1 + monocytic cells and polarize macrophages to an immune suppressive Ccr2 hi F4/80 + Cx3cr1 + CD206 + phenotype. Both monocytes and macrophages express high levels of transforming growth factor induced (Tgfbi) protein, which suppresses NK cell activity. Hedgehog inhibitor (HHi) therapy reversed CA-MSC effects, reducing myeloid cell presence and expression of Tgfbi, increasing intratumoral NK cell numbers, and restoring response to ICI therapy. Thus, CA-MSCs regulate antitumor immunity, and CA-MSC hedgehog signaling is an important target for cancer immunotherapy.
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