Modulation of T-cell activation by malignant melanoma initiating cells.
Modulation of T-cell activation by malignant melanoma initiating cells.
复制标题
DOI：
10.1158/0008-5472.can-09-1592
复制
发表时间：
2010-01-15
期刊：
影响因子：
11.2
通讯作者：
Frank MH
中科院分区：
文献类型：
--
作者：
Schatton T;Schütte U;Frank NY;Zhan Q;Hoerning A;Robles SC;Zhou J;Hodi FS;Spagnoli GC;Murphy GF;Frank MH
高免疫原性癌症，如恶性黑色素瘤，尽管存在抗肿瘤免疫，但仍能够不可阻挡地生长。这增加了一种可能性，即只有极少数致瘤的恶性细胞可能具有调节肿瘤导向的免疫激活的表型和功能特征。在这里，我们通过证明致瘤性ABCB5+恶性黑色素瘤起始细胞(MMICs)具有优先抑制IL-2依赖的T细胞激活和以B7.2依赖的方式支持调节性T(Treg)细胞诱导的能力来支持这一假说。与黑色素瘤群体相比，ABCB5+MMICs主要组织相容性复合体(MHC)I类表达水平降低，MHC II类表达异常阳性，黑色素瘤相关抗原(MAAS)MART-1、ML-IAP、NY-ESO-1和MAGE-A表达水平降低。此外，在已建立的黑色素瘤异种移植瘤和体内临床肿瘤标本中，致瘤ABCB5+亚群优先表达共刺激分子B7.2和PD-1。在免疫激活试验中，ABCB5+黑色素瘤细胞比ABCB5−细胞更有效地抑制依赖丝裂原的人外周血单核细胞的增殖和IL-2的产生。此外，与ABCB5+MMICs共培养，以B7.2信号依赖的方式增加了CD4+CD25+FoxP3+Treg细胞的丰度和丝裂原激活的PBMCs产生的IL-10。与这些发现一致，ABCB5+黑色素瘤亚群也优先抑制共培养的患者来源的同基因PBMC产生IL-2和诱导IL-10的分泌。我们的发现确定了ABCB5+黑色素瘤亚群新的T细胞调节功能，并提示MMICs在逃避抗肿瘤免疫和癌症免疫治疗耐药中的特殊作用。
Highly immunogenic cancers such as malignant melanoma are capable of inexorable tumor growth despite the presence of antitumor immunity. This raises the possibility that only a restricted minority of tumorigenic malignant cells might possess the phenotypic and functional characteristics to modulate tumor-directed immune activation. Here we provide evidence supporting this hypothesis, by demonstrating that tumorigenic ABCB5+ malignant melanoma-initiating cells (MMICs) possess the capacity to preferentially inhibit interleukin (IL)-2-dependent T cell activation and to support, in a B7.2-dependent manner, regulatory T (Treg) cell induction. Compared to melanoma bulk populations, ABCB5+ MMICs expressed lower levels of the major histocompatibility complex (MHC) class I, showed aberrant positivity for MHC class II, and exhibited lower expression levels of the melanoma-associated antigens (MAAs) MART-1, ML-IAP, NY-ESO-1, and MAGE-A. In addition, tumorigenic ABCB5+ subpopulations preferentially expressed the costimulatory molecules B7.2 and PD-1 in both established melanoma xenografts and clinical tumor specimens in vivo. In immune activation assays, ABCB5+ melanoma cells inhibited mitogen-dependent human peripheral blood mononuclear cell (PBMC) proliferation and IL-2 production more efficiently than ABCB5− populations. Moreover, coculture with ABCB5+ MMICs increased, in a B7.2 signalling-dependent manner, CD4+CD25+FoxP3+ Treg cell abundance and IL-10 production by mitogen-activated PBMCs. Consistent with these findings, ABCB5+ melanoma subsets also preferentially inhibited IL-2 production and induced IL-10 secretion by cocultured patient-derived, syngeneic PBMCs. Our findings identify novel T cell-modulatory functions of ABCB5+ melanoma subpopulations and suggest specific roles for MMICs in the evasion of antitumor immunity and in cancer immunotherapeutic resistance.