Synergistic targeting of breast cancer stem-like cells by human γδ T cells and CD8(+) T cells.
Synergistic targeting of breast cancer stem-like cells by human γδ T cells and CD8(+) T cells.
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DOI：
10.1038/icb.2017.21
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发表时间：
2017-08
影响因子：
4
通讯作者：
Eberl M
中科院分区：
文献类型：
--
作者：
Chen HC;Joalland N;Bridgeman JS;Alchami FS;Jarry U;Khan MWA;Piggott L;Shanneik Y;Li J;Herold MJ;Herrmann T;Price DA;Gallimore AM;Clarkson RW;Scotet E;Moser B;Eberl M
癌症干细胞（CSC）对现有疗法的固有抗性在很大程度上阻碍了晚期恶性肿瘤有效治疗的发展。为了帮助开发有效靶向CSC的新型免疫治疗方法，建立了一种允许可靠区分CSC和非CSC的实验模型，以研究它们与非MHC限制性γδ T细胞和抗原特异性CD 8 + T细胞的相互作用。具有乳腺CSC样细胞特征的稳定细胞系由ras转化的人乳腺上皮（HMLER）细胞产生，如通过它们的CD 44 hi CD 24 lo GD 2+表型、它们在培养物中的间充质形态和它们在非粘附条件下形成乳腺球的能力以及它们在异种移植小鼠中的强效致瘤性、自我更新和分化所证实的。用唑来膦酸或法尼基焦磷酸合成酶（FPPS）靶向短发夹RNA预处理，抑制FPPS，可克服CSC样细胞对γδ T细胞的抵抗。γδ T细胞诱导CSC样细胞上的MHC I类和CD 54/ICAM-1上调，从而增加对CD 8 + T细胞的抗原特异性杀伤的易感性。或者，使用人源化抗GD 2单克隆抗体hu14.18K322A，γδ T细胞应答可以特异性针对CSC样细胞。我们的研究结果确定了MHC限制性和非MHC限制性T细胞在根除包括乳腺CSC在内的癌细胞方面的强大协同作用。我们的研究表明，新的免疫疗法可能受益于结合γδ T细胞和CD 8 + T细胞靶向策略的双管齐下的方法，这些策略可以触发有效的先天性和肿瘤特异性适应性反应。
The inherent resistance of cancer stem cells (CSCs) to existing therapies has largely hampered the development of effective treatments for advanced malignancy. To help develop novel immunotherapy approaches that efficiently target CSCs, an experimental model allowing reliable distinction of CSCs and non-CSCs was set up to study their interaction with non-MHC-restricted γδ T cells and antigen-specific CD8+ T cells. Stable lines with characteristics of breast CSC-like cells were generated from ras-transformed human mammary epithelial (HMLER) cells as confirmed by their CD44hi CD24lo GD2+ phenotype, their mesenchymal morphology in culture and their capacity to form mammospheres under non-adherent conditions, as well as their potent tumorigenicity, self-renewal and differentiation in xenografted mice. The resistance of CSC-like cells to γδ T cells could be overcome by inhibition of farnesyl pyrophosphate synthase (FPPS) through pretreatment with zoledronate or with FPPS-targeting short hairpin RNA. γδ T cells induced upregulation of MHC class I and CD54/ICAM-1 on CSC-like cells and thereby increased the susceptibility to antigen-specific killing by CD8+ T cells. Alternatively, γδ T-cell responses could be specifically directed against CSC-like cells using the humanised anti-GD2 monoclonal antibody hu14.18K322A. Our findings identify a powerful synergism between MHC-restricted and non-MHC-restricted T cells in the eradication of cancer cells including breast CSCs. Our research suggests that novel immunotherapies may benefit from a two-pronged approach combining γδ T-cell and CD8+ T-cell targeting strategies that triggers effective innate-like and tumour-specific adaptive responses.
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影响因子：
11.2
作者：
Brown CE;Starr R;Martinez C;Aguilar B;D'Apuzzo M;Todorov I;Shih CC;Badie B;Hudecek M;Riddell SR;Jensen MC
通讯作者：
Jensen MC
影响因子：
11.2
作者：
Hollier BG;Tinnirello AA;Werden SJ;Evans KW;Taube JH;Sarkar TR;Sphyris N;Shariati M;Kumar SV;Battula VL;Herschkowitz JI;Guerra R;Chang JT;Miura N;Rosen JM;Mani SA
通讯作者：
Mani SA
DOI：
10.1038/nri2635
发表时间：
2009-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1007/s00432-012-1311-2
发表时间：
2013-01-01
影响因子：
3.6
作者：
Liao, Tian;Kaufmann, Andreas M.;Albers, Andreas E.
通讯作者：
Albers, Andreas E.
DOI：
10.1073/pnas.0810059106
发表时间：
2009-02-17
影响因子：
11.1
作者：
Brandes, Marlene;Willimann, Katharina;Moser, Bernhard
通讯作者：
Moser, Bernhard