Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer-initiating cells.
Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer-initiating cells.
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DOI：
10.1186/s12885-018-4389-3
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发表时间：
2018-04-26
期刊：
影响因子：
3.8
通讯作者：
Morris JC
中科院分区：
文献类型：
--
作者：
Morrison BJ;Steel JC;Morris JC
有人提出，癌症的建立、维持和复发可能归因于一组独特的肿瘤细胞，称为癌症起始细胞(CICs)，其中可能包括假定的癌症干细胞样细胞的特征。对肺癌的研究表明，通过将肿瘤细胞在无血清悬浮液中培养成肿瘤球体，此类细胞可以在体外得到丰富和繁殖。CICs的表型、干细胞样特性以及它们在建立肿瘤和维持肿瘤生长中的作用已被鉴定为CICs。对CICs与免疫系统的相互作用知之甚少。我们从小鼠TC-1肺癌细胞中构建了富含CIC的肿瘤微球，表达了HPV-16 E6/E7抗原，并在体外和体内检测了它们对抗肿瘤免疫反应的敏感性。与非CICs相比，TC-1 CICs的表面主要组织相容性复合体(MHC)-I分子的表达减少。我们同样确定了在CICs培养条件下培养的六种人肺癌细胞系中有五种MHC-I的表达降低。在体内，富含CICs的TC-1细胞对HPV16E6/E7多肽疫苗介导的杀伤具有抵抗力。我们发现，与未富含CIC的受试者相比，接种CIC富集型肿瘤微球的小鼠存活时间更短，CD8+肿瘤浸润性淋巴细胞显著减少。此外，来自免疫小鼠的培养的细胞毒性T淋巴细胞(CTL)与未浓缩的TC-1细胞相比，对富含CICs的TC-1细胞的裂解能力降低。经干扰素-γ处理后，CIC强化和未强化的TC-1细胞均表达相似水平的MHC-I，并且CIC上MHC-I的表达增加导致CTL介导的肿瘤杀伤作用增强，并改善小鼠的无瘤生存。这些结果表明，CICs表达MHC-I分子的减弱代表了CICs逃避免疫识别的一种潜在策略，针对CICs的成功免疫治疗策略的发展可能通过增强CIC MHC-I的表达来降低其对T细胞介导的免疫检测的抵抗力。本文的在线版本(10.1186/s12885-0184389-3)包含向授权用户提供的补充材料。
It has been proposed that cancer establishment, maintenance, and recurrence may be attributed to a unique population of tumor cells termed cancer-initiating cells (CICs) that may include characteristics of putative cancer stem cell-like cells. Studies in lung cancer have shown that such cells can be enriched and propagated in vitro by culturing tumor cells in serum-free suspension as tumorspheres. CICs have been characterized for their phenotype, stem cell-like qualities, and their role in establishing tumor and maintaining tumor growth. Less is known about the interaction of CICs with the immune system. We established CIC-enriched tumorspheres from murine TC-1 lung cancer cells, expressing human papillomavirus 16 (HPV-16) E6/E7 antigens, and evaluated their susceptibility to antitumor immune responses both in vitro and in vivo. TC-1 CICs demonstrated reduced expression of surface major histocompatibility complex (MHC)-I molecules compared to non-CICs. We similarly determined decreased MHC-I expression in five of six human lung cancer cell lines cultured under conditions enriching for CICs. In vivo, TC-1 cells enriched for CICs were resistant to human papillomavirus 16 E6/E7 peptide vaccine-mediated killing. We found that vaccinated mice challenged with CIC enriched tumorspheres demonstrated shorter survivals and showed significantly fewer CD8+ tumor infiltrating lymphocytes compared to CIC non-enriched challenged mice. Furthermore, cultured cytotoxic T lymphocytes (CTLs) from vaccinated mice demonstrated reduced capacity to lyse TC-1 cells enriched for CICs compared to non-enriched TC-1 cells. Following treatment with IFN-γ, both CIC enriched and non-enriched TC-1 cells expressed similar levels of MHC-I, and the increased MHC-I expression on CICs resulted in greater CTL-mediated tumor lysis and improved tumor-free survival in mice. These results suggest that the attenuated expression of MHC-I molecules by CICs represents a potential strategy of CICs to escape immune recognition, and that the development of successful immunotherapy strategies targeting CICs may decrease their resistance to T cell-mediated immune detection by enhancing CIC MHC-I expression. The online version of this article (10.1186/s12885-018-4389-3) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Smart CE;Morrison BJ;Saunus JM;Vargas AC;Keith P;Reid L;Wockner L;Askarian-Amiri M;Sarkar D;Simpson PT;Clarke C;Schmidt CW;Reynolds BA;Lakhani SR;Lopez JA
通讯作者：
Lopez JA
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：
5.4
作者：
Morrison, Brian J.;Morris, John C.;Steel, Jason C.
通讯作者：
Steel, Jason C.
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
6.4
作者：
Avril, Tony;Vauleon, Elodie;Quillien, Veronique
通讯作者：
Quillien, Veronique