Background Cancer mutations generate novel (neo-)peptides recognised by T cells, but the determinants of recognition are not well characterised. The difference in predicted class I major histocompatibility complex (MHC-I) binding affinity between wild-type and corresponding mutant peptides (differential agretopicity index; DAI) may reflect clinically relevant cancer peptide immunogenicity. Our aim was to explore the relationship between DAI, measures of immune infiltration and patient outcomes in advanced cancer. Patients and methods Cohorts of patients with advanced non-small-cell lung cancer (NSCLC; LUAD, n = 66) and melanoma (SKCM, n = 72) were obtained from The Cancer Genome Atlas. Three additional cohorts of immunotherapy treated patients with advanced melanoma (total n = 131) and NSCLC (n = 31) were analysed. Neopeptides and their clonal status were defined using genomic data. MHC-I binding affinity was predicted for each neopeptide and DAI values summarised as the sample mean DAI. Correlations between mean DAI and markers of immune activity were evaluated using measures of lymphocyte infiltration and immune gene expression. Results In univariate and multivariate analyses, mean DAI significantly correlated with overall survival in 3/5 cohorts, with evidence of superiority over nonsynonymous mutational and neoantigen burden. In these cohorts, the effect was seen for mean DAI of clonal but not subclonal peptides. In SKCM, the association between mean DAI and survival bordered significance (P = 0.068), reaching significance in an immunotherapy-treated melanoma cohort (P = 0.003). Mean DAI but not mutational nor neoantigen burden was positively correlated with independently derived markers of immune infiltration in both SKCM (P = 0.027) and LUAD (P = 0.024). Conclusions The association between mean DAI, survival and measures of immune activity support the hypothesis that DAI is a determinant of cancer peptide immunogenicity. Investigation of DAI as a marker of immunologically relevant peptides in further datasets and future clinical studies of neoantigen based immunotherapies is warranted.

中文翻译：

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突变肽对 MHC I 类的差异结合亲和力是晚期肺癌和黑色素瘤存活率的预测因子。

背景癌症突变产生了被 T 细胞识别的新型（新）肽，但识别的决定因素尚未得到很好的表征。野生型和相应突变肽之间预测的 I 类主要组织相容性复合物 (MHC-I) 结合亲和力的差异（差异异位性指数；DAI）可能反映了临床相关的癌症肽免疫原性。我们的目的是探索 DAI、免疫浸润测量和晚期癌症患者预后之间的关系。患者和方法 晚期非小细胞肺癌 (NSCLC; LUAD, n = 66) 和黑色素瘤 (SKCM, n = 72) 患者的队列来自癌症基因组图谱。分析了另外三个接受免疫疗法治疗的晚期黑色素瘤（总共 n = 131）和 NSCLC（n = 31）的患者队列。使用基因组数据定义新肽及其克隆状态。预测每种新肽的 MHC-I 结合亲和力，并将 DAI 值总结为样品平均 DAI。使用淋巴细胞浸润和免疫基因表达的测量来评估平均 DAI 和免疫活性标志物之间的相关性。结果在单变量和多变量分析中，平均 DAI 与 3/5 队列的总生存期显着相关，有证据表明其优于非同义突变和新抗原负担。在这些队列中，观察到克隆肽的平均 DAI 而非亚克隆肽的影响。在 SKCM 中，平均 DAI 与存活率之间的关联具有显着性（P = 0.068），在免疫治疗治疗的黑色素瘤队列中达到显着性（P = 0.003）。在 SKCM (P = 0.027) 和 LUAD (P = 0.024) 中，平均 DAI 而非突变或新抗原负荷与独立衍生的免疫浸润标志物呈正相关。结论 平均 DAI、存活率和免疫活性测量之间的关联支持 DAI 是癌症肽免疫原性决定因素的假设。有必要在进一步的数据集中研究 DAI 作为免疫相关肽的标志物，并有必要对基于新抗原的免疫疗法进行未来的临床研究。