Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany.
Weill Cornell Medical College, New York, New York.
Gastroenterology. 2021 Oct;161(4):1288-1302.e13. doi: 10.1053/j.gastro.2021.06.073. Epub 2021 Jul 2.
BACKGROUND & AIMS: DNA mismatch repair deficiency 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. Individuals with LS 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 yet been demonstrated.
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 4 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 4 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 preclinical findings support a clinical strategy of recurrent FSP neoantigen vaccination for LS cancer immunoprevention.
DNA 错配修复缺陷会导致微卫星不稳定（MSI）。具有 MSI 的细胞会积累大量移码突变。影响癌症相关基因的移码突变可能会促进肿瘤发生，因此存在于独立发生的 MSI 肿瘤中。因此，这些反复出现的移码突变可以产生共同的免疫原性移码肽（FSP），它们是针对 MSI 癌症的疫苗的理想候选物。错配修复基因的致病性种系变异会导致林奇综合征（LS），这是一种影响全球约 2000 至 2500 万人的遗传性癌症综合征。LS 患者患 MSI 癌症的风险很高。先前，我们在一项针对 MSI 结直肠癌病史患者的 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，FSP 疫苗接种在 LS 情况下的癌症预防效果尚未得到证明。
建立了一个包含 488235 个小鼠编码单核苷酸重复的全基因组数据库，从中根据重复长度、基因表达和突变频率选择了一组候选物。通过计算机预测、体内免疫原性测试和表位作图来鉴定 FSP 疫苗接种的候选物。
我们鉴定了 4 个共享的 FSP 新抗原（Nacad[FSP-1]、Maz[FSP-1]、Senp6[FSP-1]、Xirp1[FSP-1]），它们在未致敏的 C57BL/6 小鼠中诱导了 CD4/CD8 T 细胞反应。使用 VCMsh2 小鼠，该小鼠在肠道中条件性敲除了 Msh2，会发展为肠道癌，我们表明，仅用 4 个 FSP 组合进行疫苗接种可显著增加 FSP 特异性适应性免疫应答，减少肠道肿瘤负担，并延长总生存期。与单独进行 FSP 疫苗接种相比，FSP 疫苗接种与每天使用萘普生治疗相结合可更有效地增强免疫反应、延迟肿瘤生长并延长生存期。
我们的临床前研究结果支持将复发性 FSP 新抗原疫苗接种用于 LS 癌症免疫预防的临床策略。
