Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada; Department of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada.
Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada.
Cell Rep. 2022 Aug 16;40(7):111241. doi: 10.1016/j.celrep.2022.111241.
Previous reports showed that mouse vaccination with pluripotent stem cells (PSCs) induces durable anti-tumor immune responses via T cell recognition of some elusive oncofetal epitopes. We characterize the MHC I-associated peptide (MAP) repertoire of human induced PSCs (iPSCs) using proteogenomics. Our analyses reveal a set of 46 pluripotency-associated MAPs (paMAPs) absent from the transcriptome of normal tissues and adult stem cells but expressed in PSCs and multiple adult cancers. These paMAPs derive from coding and allegedly non-coding (48%) transcripts involved in pluripotency maintenance, and their expression in The Cancer Genome Atlas samples correlates with source gene hypomethylation and genomic aberrations common across cancer types. We find that several of these paMAPs were immunogenic. However, paMAP expression in tumors coincides with activation of pathways instrumental in immune evasion (WNT, TGF-β, and CDK4/6). We propose that currently available inhibitors of these pathways could synergize with immune targeting of paMAPs for the treatment of poorly differentiated cancers.
先前的报告表明，通过 T 细胞识别一些难以捉摸的癌胚抗原表位，用多能干细胞（PSCs）对小鼠进行疫苗接种可诱导持久的抗肿瘤免疫反应。我们使用蛋白质基因组学来描述人类诱导多能干细胞（iPSCs）的 MHC I 相关肽（MAP）库。我们的分析揭示了一组 46 种与多能性相关的 MAP（paMAP），它们不存在于正常组织和成人干细胞的转录组中，但在 PSCs 和多种成人癌症中表达。这些 paMAP 来源于参与维持多能性的编码和据称非编码（48%）转录本，并且它们在癌症基因组图谱样本中的表达与源基因低甲基化和常见于多种癌症类型的基因组异常相关。我们发现其中一些 paMAP 具有免疫原性。然而，paMAP 在肿瘤中的表达与在免疫逃逸（WNT、TGF-β 和 CDK4/6）中起重要作用的途径的激活相吻合。我们提出，目前这些途径的抑制剂与 paMAP 的免疫靶向治疗相结合可能协同作用，用于治疗分化不良的癌症。
