Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA.
Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA; The Blavatnik Family Women's Health Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Cell. 2020 Dec 10;183(6):1634-1649.e17. doi: 10.1016/j.cell.2020.11.004. Epub 2020 Nov 30.
Microsatellite instability-high (MSI-H) tumors are characterized by high tumor mutation burden and responsiveness to checkpoint blockade. We identified tumor-specific frameshifts encoding multiple epitopes that originated from indel mutations shared among patients with MSI-H endometrial, colorectal, and stomach cancers. Epitopes derived from these shared frameshifts have high population occurrence rates, wide presence in many tumor subclones, and are predicted to bind to the most frequent MHC alleles in MSI-H patient cohorts. Neoantigens arising from these mutations are distinctly unlike self and viral antigens, signifying novel groups of potentially highly immunogenic tumor antigens. We further confirmed the immunogenicity of frameshift peptides in T cell stimulation experiments using blood mononuclear cells isolated from both healthy donors and MSI-H cancer patients. Our study uncovers the widespread occurrence and strong immunogenicity of tumor-specific antigens derived from shared frameshift mutations in MSI-H cancer and Lynch syndrome patients, suitable for the design of common "off-the-shelf" cancer vaccines.
微卫星不稳定高（MSI-H）肿瘤的特征是高肿瘤突变负担和对检查点阻断的反应性。我们鉴定了肿瘤特异性移码，其编码源自 MSI-H 子宫内膜癌、结直肠癌和胃癌患者之间共享的插入缺失突变的多个表位。源自这些共享移码的表位具有高人群发生率，广泛存在于许多肿瘤亚克隆中，并预测与 MSI-H 患者队列中最常见的 MHC 等位基因结合。这些突变产生的新抗原与自身和病毒抗原明显不同，代表了新的潜在高度免疫原性肿瘤抗原群体。我们进一步通过使用从健康供体和 MSI-H 癌症患者分离的血液单核细胞在 T 细胞刺激实验中证实了移码肽的免疫原性。我们的研究揭示了 MSI-H 癌症和 Lynch 综合征患者中源自共享移码突变的肿瘤特异性抗原的广泛发生和强免疫原性，适合设计通用的“现成”癌症疫苗。
