Immunoprevention of chemical carcinogenesis through early recognition of oncogene mutations.
Immunoprevention of chemical carcinogenesis through early recognition of oncogene mutations.
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通过早期识别癌基因突变对化学癌变的免疫预防。
DOI：
10.4049/jimmunol.1402125
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发表时间：
2015-03-15
期刊：
影响因子：
--
通讯作者：
Timares L
中科院分区：
文献类型：
--
作者：
Nasti TH;Rudemiller KJ;Cochran JB;Kim HK;Tsuruta Y;Fineberg NS;Athar M;Elmets CA;Timares L
环境致癌物诱发肿瘤的预防尚未实现。由多环芳烃如7，12-二甲基苯并蒽（DMBA）产生的皮肤肿瘤通常具有H-ras点突变，这表明它是早期免疫监视的不良靶点。焦磷酸测序和等位基因特异性PCR技术的应用建立了基因组中的突变和Mut H-ras基因的表达可以检测到早在DMBA应用后一天。此外，DMBA致敏提高了Mut H-ras表位特异性CTL，能够消除Mut H-ras+肿瘤前皮肤细胞，表明免疫监视是正常诱导的，但由于效应池大小不足和/或免疫抑制可能无效。为了测试对单个Mut H-ras表位具有特异性的CD 8 T细胞的选择性预扩增是否足以预防肿瘤，设计了基于MHC I类表位聚焦的慢病毒感染的树突状细胞（DC）和DNA的疫苗以偏向CTL而不是Treg诱导。Mut H-ras而非野生型H-ras表位聚焦疫苗接种产生特异性CTL，并在预防和治疗环境中抑制DMBA诱导的肿瘤起始、生长和进展。转移的Mut H-ras特异性效应子诱导快速肿瘤消退，克服了荷瘤小鼠中建立的肿瘤抑制。这些研究支持进一步评估致癌突变作为早期肿瘤特异性免疫原性表位的潜力，以扩大相关的免疫调节效应子，从而阻断肿瘤形成，而不是治疗已建立的肿瘤。
Prevention of tumors induced by environmental carcinogens has not been achieved. Skin tumors produced by polyaromatic hydrocarbons, such as 7,12-dimethylbenzanthracene (DMBA) often harbor an H-ras point mutation, suggesting that it is a poor target for early immune surveillance. The application of pyrosequencing and allele-specific PCR techniques established that mutations in the genome and expression of the Mut H-ras gene could be detected as early as one day after DMBA application. Further, DMBA sensitization raised Mut H-ras epitope-specific CTLs capable of eliminating Mut H-ras+ pre-neoplastic skin cells, demonstrating that immunosurveillance is normally induced but may be ineffective due to insufficient effector pool size and/or immune suppression. To test whether selective pre-expansion of CD8 T cells with specificity for the single Mut H-ras epitope was sufficient for tumor prevention, MHC class I-epitope-focused lentivector-infected dendritic cell (DC)- and DNA-based vaccines were designed to bias toward CTL rather than Treg induction. Mut H-ras but not wild-type H-ras epitope-focused vaccination generated specific CTL and inhibited DMBA-induced tumor initiation, growth and progression in preventative and therapeutic settings. Transferred Mut H-ras-specific effectors induced rapid tumor regression, overcoming established tumor suppression in tumor bearing mice. These studies support further evaluation of oncogenic mutations for their potential to act as early tumor-specific, immunogenic epitopes to expand relavent immunesurviellance effectors in order to block tumor formation, rather than treating established tumors.
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影响因子：
12.4
作者：
Andersson, HA;Barry, MA
通讯作者：
Barry, MA
影响因子：
64.8
作者：
Matsushita, Hirokazu;Vesely, Matthew D.;Koboldt, Daniel C.;Rickert, Charles G.;Uppaluri, Ravindra;Magrini, Vincent J.;Arthur, Cora D.;White, J. Michael;Chen, Yee-Shiuan;Shea, Lauren K.;Hundal, Jasreet;Wendl, Michael C.;Demeter, Ryan;Wylie, Todd;Allison, James P.;Smyth, Mark J.;Old, Lloyd J.;Mardis, Elaine R.;Schreiber, Robert D.
通讯作者：
Schreiber, Robert D.
DOI：
10.1073/pnas.92.22.10422
发表时间：
1995-10-24
影响因子：
11.1
作者：
CHAKRAVARTI, D;PELLING, JC;ROGAN, EG
通讯作者：
ROGAN, EG
影响因子：
46.9
作者：
Fan, HR;Lin, Q;Khavari, PA
通讯作者：
Khavari, PA
影响因子：
3.7
作者：
Morlan J;Baker J;Sinicropi D
通讯作者：
Sinicropi D