MUC1 Vaccines, Comprised of Glycosylated or Non-Glycosylated Peptides or Tumor-Derived MUC1, Can Circumvent Immunoediting to Control Tumor Growth in MUC1 Transgenic Mice.
MUC1 Vaccines, Comprised of Glycosylated or Non-Glycosylated Peptides or Tumor-Derived MUC1, Can Circumvent Immunoediting to Control Tumor Growth in MUC1 Transgenic Mice.
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DOI：
10.1371/journal.pone.0145920
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Gendler SJ
中科院分区：
文献类型：
--
作者：
Lakshminarayanan V;Supekar NT;Wei J;McCurry DB;Dueck AC;Kosiorek HE;Trivedi PP;Bradley JM;Madsen CS;Pathangey LB;Hoelzinger DB;Wolfert MA;Boons GJ;Cohen PA;Gendler SJ
生产针对MUC1的决定性疫苗仍然具有挑战性，MUC1是一种广泛表达于胰腺、乳腺和其他肿瘤的肿瘤相关抗原。利用临床相关的小鼠模型，我们排除了不可逆的T细胞耐受性、亲和力不足以及T细胞无法识别异常糖基化的肿瘤MUC1等原因。相反，每一种测试的MUC1制剂，即使是非糖基化的合成9聚体多肽，都会诱导产生干扰素伽玛的CD4+和CD8+T细胞，识别包括肿瘤相关MUC1在内的糖基化变体。只要在肿瘤攻击后重复接种，合成多肽疫苗就能提供保护。挑战后未能重新接种与肿瘤MUC1和MHC分子下调有关。令人惊讶的是，直接将表达MUC1的肿瘤与MUC1-高免疫T细胞混合并不能防止肿瘤生长或MUC1免疫编辑，而在肿瘤混合之前体外激活高免疫T细胞使其治愈。因此，替代T细胞在肿瘤床外的预激活，无论是在培养中还是通过重复接种，都可以克服肿瘤逃逸。
It remains challenging to produce decisive vaccines against MUC1, a tumor-associated antigen widely expressed by pancreas, breast and other tumors. Employing clinically relevant mouse models, we ruled out such causes as irreversible T-cell tolerance, inadequate avidity, and failure of T-cells to recognize aberrantly glycosylated tumor MUC1. Instead, every tested MUC1 preparation, even non-glycosylated synthetic 9mer peptides, induced interferon gamma-producing CD4+ and CD8+ T-cells that recognized glycosylated variants including tumor-associated MUC1. Vaccination with synthetic peptides conferred protection as long as vaccination was repeated post tumor challenge. Failure to revaccinate post challenge was associated with down-regulated tumor MUC1 and MHC molecules. Surprisingly, direct admixture of MUC1-expressing tumor with MUC1-hyperimmune T-cells could not prevent tumor outgrowth or MUC1 immunoediting, whereas ex vivo activation of the hyperimmune T-cells prior to tumor admixture rendered them curative. Therefore, surrogate T-cell preactivation outside the tumor bed, either in culture or by repetitive vaccination, can overcome tumor escape.
影响因子：
3.7
作者：
Sugiura D;Denda-Nagai K;Takashima M;Murakami R;Nagai S;Takeda K;Irimura T
通讯作者：
Irimura T