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首页> 外文期刊>Journal for ImmunoTherapy of Cancer >Immunopeptidomics of colorectal cancer organoids reveals a sparse HLA class I neoantigen landscape and no increase in neoantigens with interferon or MEK-inhibitor treatment
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Immunopeptidomics of colorectal cancer organoids reveals a sparse HLA class I neoantigen landscape and no increase in neoantigens with interferon or MEK-inhibitor treatment

机译：大肠癌类器官的免疫肽组学显示HLA I类新抗原稀疏，且干扰素或MEK抑制剂治疗的新抗原没有增加

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Abstract BackgroundPatient derived organoids (PDOs) can be established from colorectal cancers (CRCs) as in vitro models to interrogate cancer biology and its clinical relevance. We applied mass spectrometry (MS) immunopeptidomics to investigate neoantigen presentation and whether this can be augmented through interferon gamma (IFNγ) or MEK-inhibitor treatment.MethodsFour microsatellite stable PDOs from chemotherapy refractory and one from a treatment na?ve CRC were expanded to replicates with 100 million cells each, and HLA class I and class II peptide ligands were analyzed by MS.ResultsWe identified an average of 9936 unique peptides per PDO which compares favorably against published immunopeptidomics studies, suggesting high sensitivity. Loss of heterozygosity of the HLA locus was associated with low peptide diversity in one PDO. Peptides from genes without detectable expression by RNA-sequencing were rarely identified by MS. Only 3 out of 612 non-silent mutations encoded for neoantigens that were detected by MS. In contrast, computational HLA binding prediction estimated that 304 mutations could generate neoantigens. One hundred ninety-six of these were located in expressed genes, still exceeding the number of MS-detected neoantigens 65-fold. Treatment of four PDOs with IFNγ upregulated HLA class I expression and qualitatively changed the immunopeptidome, with increased presentation of IFNγ-inducible genes. HLA class II presented peptides increased dramatically with IFNγ treatment. MEK-inhibitor treatment showed no consistent effect on HLA class I or II expression or the peptidome. Importantly, no additional HLA class I or II presented neoantigens became detectable with any treatment.ConclusionsOnly 3 out of 612 non-silent mutations encoded for neoantigens that were detectable by MS. Although MS has sensitivity limits and biases, and likely underestimated the true neoantigen burden, this established a lower bound of the percentage of non-silent mutations that encode for presented neoantigens, which may be as low as 0.5%. This could be a reason for the poor responses of non-hypermutated CRCs to immune checkpoint inhibitors. MEK-inhibitors recently failed to improve checkpoint-inhibitor efficacy in CRC and the observed lack of HLA upregulation or improved peptide presentation may explain this.
机译：摘要背景可从结直肠癌（CRC）建立体外源模型类器官（PDO），以询问癌症生物学及其临床意义。我们应用质谱（MS）免疫肽组学来研究新抗原的呈递，以及是否可以通过干扰素γ（IFNγ）或MEK抑制剂的治疗来增强新抗原的呈递方法。结果我们鉴定出每个PDO平均含有9936个独特的肽，与已发表的免疫肽组学研究相比，具有很高的敏感性，从而对HLA I类和II类肽配体进行了质谱分析。 HLA基因座杂合性的丧失与一个PDO中肽多样性低有关。 MS很少鉴定出无法通过RNA测序检测到的基因中的肽。 MS检测到的612个非沉默突变中，只有3个编码为新抗原。相比之下，计算HLA结合预测估计304个突变可产生新抗原。其中的166个位于表达的基因中，仍然超过MS检测到的新抗原的65倍。用IFNγ处理四个PDO会上调HLA I类表达并定性地改变免疫肽组，并增加IFNγ诱导基因的表达。 HLA II类提出的肽随IFNγ处理而显着增加。 MEK抑制剂治疗对HLA I类或II类表达或肽组没有一致的作用。重要的是，在任何处理下都无法检测到其他呈递的HLA I类或II类新抗原。结论在MS可检测到的612个非沉默突变中，只有3个编码为新抗原。尽管MS具有敏感性限制和偏见，并且可能低估了真正的新抗原负担，但这为编码呈递的新抗原的非沉默突变所占的百分比确定了下限，可能低至0.5％。这可能是非超突变CRC对免疫检查点抑制剂反应不良的原因。 MEK抑制剂最近未能改善CRC中检查点抑制剂的功效，并且观察到的HLA缺乏上调或肽呈递改善可能解释了这一点。

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