Profiling cancer neoantigen repertoires and validating immunotherapy targets

描述(由申请人提供)：癌症选择性或特异性编码序列的翻译产物自然适合作为几乎任何治疗方式的靶点，因为它们有可能成为靶点，而不会对正常组织产生不利影响。我们推测，在TCGA中首次发现的流行的癌症选择性转录本(CST)的翻译产物可能富含由恶性细胞表面的MHC I或II类分子选择性递送的新抗原，因此是免疫治疗的有吸引力的靶点。最有希望的靶点可以通过一种计算方法来确定，该方法将TCGA RNA序列数据与描绘体细胞组织的精心策划的数据资源以及宝贵的本地数据资源整合在一起，使我们能够推断CST的翻译活性，并预测哪些CST不是来自肿瘤浸润性细胞。我们的初步工作表明，在我们评估的几种癌症中，我们可以在每一种癌症中识别出大量的CST，它们(I)在多个不同患者的癌症组织中表达，(Ii)在未转化的成人躯体组织中明显缺失，(Iii)来自实体肿瘤的恶性细胞成分，以及(Iv)具有翻译活性。我们确定的CSTs包括一系列以前被证明可以产生免疫原肽的改变家族，这些改变可以引发CD8 T细胞免疫反应，并且已经在这些器官部位的癌症的关键基因中发现了它们。虽然在癌症组织样本中鉴定明显具有癌症选择性的转录本并不能保证新抗原的存在，但它确实为进一步分析提供了一个具有成本效益和逻辑的起点，因为我们的项目将：1)针对每个TCGA癌症部位估计流行的CST并预测在卵巢癌、结肠癌和肺癌患者中发现的CST的翻译状态。目的2)对于卵巢癌、结肠癌、肺癌，确定哪些预测的肿瘤选择性多肽含有可被CD4或CD8T细胞识别的表位。目的3)前瞻性验证肺癌抗原，通过在第三阶段试验中收集的样本中确定T细胞抑制通路中断后患者的免疫反应是否增强。

DESCRIPTION (provided by applicant): The translation products of cancer-selective or -specific coding sequences are naturally suited for development as targets for virtually any therapeutic modality because of their potential to be targeted without adversely affecting normal tissues. We hypothesize that the translation products of prevalent cancer-selective transcripts (CSTs) first identified in the TCGA may be enriched for neo-antigens that are selectively presented by MHC class I or II molecules on the surface of malignant cells, and therefor represent attractive targets for immunotherapy. The most highly promising targets can be identified by a computational approach that integrates the TCGA RNA sequence data with well curated data resources profiling somatic tissues and with valuable local data resources that allow us to infer the translational activity of the CSTs and predict which CSTs are that are not derived from tumor infiltrating cells. Our preliminary work shows that we can identify, in each of several cancers we have evaluated, large numbers of CSTs that are (i) expressed in cancer tissues from multiple different patients, (ii) apparently absent in untransformed adult somatic tissues, and (iii) are derived from malignant cell component of the solid tumor, and (iv) are translationally active. CSTs we identify include families of alterations that have previously been shown to generate immunogenic peptides that can elicit CD8+ T cell immune responses, and they have been found in genes of central importance to cancers of those organ sites. While the identification of an apparently cancer-selective transcript in cancer tissue samples does not guarantee the presence of a neoantigen, it does provide a cost-effective and logical starting point for further analysis given the availability of proven high throughput verification approaches Our project will: Aim 1) for each TCGA cancer site estimate prevalent CSTs and also predict the translation state for CSTs identified in ovarian, colon, and lung cancer patients. Aim 2) for ovarian, colon, lung cancer identify which predicted cancer-selective polypeptides harbor epitopes that are recognized by CD4+ or CD8+ T Cells. Aim 3) prospectively validate lung cancer antigens by determining whether patient immune-response is enhanced following disruption of T cell inhibitory pathways in samples collected from Phase III trials.