Recurrent Frameshift Neoantigen Vaccine Elicits Protective Immunity With Reduced Tumor Burden and Improved Overall Survival in a Lynch Syndrome Mouse Model.
Recurrent Frameshift Neoantigen Vaccine Elicits Protective Immunity With Reduced Tumor Burden and Improved Overall Survival in a Lynch Syndrome Mouse Model.
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DOI：
10.1053/j.gastro.2021.06.073
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发表时间：
2021-10
期刊：
影响因子：
29.4
通讯作者：
中科院分区：
文献类型：
--
作者：
DNA错配修复缺陷(MMRD)导致微卫星不稳定性(MSI)。携带MSI的细胞积累了大量移码突变。影响癌症相关基因的移码突变可能促进肿瘤的发生，因此，在独立发生的MSI肿瘤中是共有的。因此，这种反复发生的移码突变可以产生共享的免疫原性移码多肽(FSP)，这些FSP代表了MSI癌症疫苗的理想候选者。错配修复基因的致病胚系变异会导致Lynch综合征(LS)，这是一种遗传性癌症综合征，全球约有2000万至2500万人受到影响。LS患者罹患MSI癌的风险很高。此前，我们在有MSI结直肠癌病史的I/IIa期临床试验中证明了基于FSP的疫苗的安全性和免疫原性。然而，在LS的情况下接种FSP疫苗的癌症预防效果迄今尚未被证明。建立了488,235只小鼠编码单核苷酸重复序列的全基因组数据库，根据重复长度、基因表达和突变频率选择了一组候选序列。在电子预测中，使用体内免疫原性测试和表位映射来确定FSP疫苗的候选疫苗。我们鉴定了四个共同的FSP新抗原[Nacad(FSP-1)，Maz(FSP-1)，Senp6(FSP-1)，Xirp1(FSP-1)]，它们能诱导幼稚C57BL/6小鼠的CD4/CD8 T细胞反应。使用VCMsh2小鼠，这些小鼠在肠道中有条件地敲除Msh2并患上肠癌，我们发现只接种四种FSP的疫苗显著增加了FSP特异性的获得性免疫，减少了肠道肿瘤负担，并延长了总的生存时间。与单独接种FSP疫苗相比，联合应用FSP疫苗可增强免疫反应、延缓肿瘤生长和延长生存期。我们的临床前研究结果支持反复接种FSP新抗原疫苗用于LS癌免疫预防的临床策略。
DNA mismatch repair deficiency (MMRD) drives microsatellite instability (MSI). Cells with MSI accumulate numerous frameshift mutations. Frameshift mutations affecting cancer-related genes may promote tumorigenesis and, therefore, are shared among independently arising MSI tumors. Consequently, such recurrent frameshift mutations can give rise to shared immunogenic frameshift peptides (FSPs) that represent ideal candidates for a vaccine against MSI cancer. Pathogenic germline variants of mismatch repair genes cause Lynch syndrome (LS), a hereditary cancer syndrome affecting approximately 20–25 million individuals worldwide. LS individuals are at high risk of developing MSI cancer. Previously, we demonstrated safety and immunogenicity of an FSP-based vaccine in a Phase I/IIa clinical trial in patients with a history of MSI colorectal cancer. However, the cancer-preventive effect of FSP vaccination in the scenario of LS has not been demonstrated so far. A genome-wide database of 488,235 mouse coding mononucleotide repeats was established, from which a set of candidates was selected based on repeat length, gene expression and mutation frequency. In silico prediction, in vivo immunogenicity testing and epitope mapping was used to identify candidates for FSP vaccination. We identified four shared FSP neoantigens [Nacad(FSP-1), Maz(FSP-1), Senp6(FSP-1), Xirp1(FSP-1)] that induced CD4/CD8 T cell responses in naïve C57BL/6 mice. Using VCMsh2 mice, which have a conditional knockout of Msh2 in the intestinal tract and develop intestinal cancer, we showed vaccination with a combination of only four FSPs significantly increased FSP-specific adaptive immunity, reduced intestinal tumor burden and prolonged overall survival. Combination of FSP vaccination with daily naproxen treatment potentiated immune response, delayed tumor growth and prolonged survival even more effectively than FSP vaccination alone. Our pre-clinical findings support a clinical strategy of recurrent FSP neoantigen vaccination for LS cancer immunoprevention.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
168.9
作者：
Burn, John;Gerdes, Anne-Marie;Macrae, Finlay;Mecklin, Jukka-Pekka;Moeslein, Gabriela;Olschwang, Sylviane;Eccles, Diane;Evans, D. Gareth;Maher, Eamonn R.;Bertario, Lucio;Bisgaard, Marie-Luise;Dunlop, Malcolm G.;Ho, Judy W. C.;Hodgson, Shirley V.;Lindblom, Annika;Lubinski, Jan;Morrison, Patrick J.;Murday, Victoria;Ramesar, Raj;Side, Lucy;Scott, Rodney J.;Thomas, Huw J. W.;Vasen, Hans F.;Barker, Gail;Crawford, Gillian;Elliott, Faye;Movahedi, Mohammad;Pylvanainen, Kirsi;Wijnen, Juul T.;Fodde, Riccardo;Lynch, Henry T.;Mathers, John C.;Bishop, D. Timothy
通讯作者：
Bishop, D. Timothy
影响因子：
12.3
作者：
Tosti E;Katakowski JA;Schaetzlein S;Kim HS;Ryan CJ;Shales M;Roguev A;Krogan NJ;Palliser D;Keogh MC;Edelmann W
通讯作者：
Edelmann W
影响因子：
30.8
作者：
HEMMINKI, A;PELTOMAKI, P;AALTONEN, LA
通讯作者：
AALTONEN, LA
影响因子：
64.5
作者：
FISHEL, R;LESCOE, MK;KOLODNER, R
通讯作者：
KOLODNER, R