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标进行开发，因为它们具有被靶向而不会对正常组织产生不利影响的潜力。我们假设，首先在 TCGA 中鉴定出的流行癌症选择性转录本 (CST) 的翻译产物可能富含由 MHC I 类或 II 类分子选择性呈递到恶性细胞表面的新抗原，因此代表了免疫治疗的有吸引力的靶点。最有希望的靶点可以通过计算方法来识别，该方法将 TCGA RNA 序列数据与精心策划的体细胞组织分析数据资源和宝贵的本地数据资源相结合，使我们能够推断 CST 的翻译活性并预测哪些 CST 不是源自肿瘤浸润细胞。我们的初步工作表明，我们可以在我们评估的几种癌症中鉴定出大量 CST，这些 CST（i）在来自多个不同患者的癌症组织中表达，（ii）在未转化的成人体细胞组织中明显不存在，（iii）源自实体瘤的恶性细胞成分，并且（iv）具有翻译活性。我们识别的 CST 包括先前已被证明可产生可引发 CD8 T 细胞免疫反应的免疫原性肽的改变家族，并且它们已在对这些器官部位的癌症至关重要的基因中被发现。虽然在癌症组织样本中鉴定出明显的癌症选择性转录本并不能保证新抗原的存在，但考虑到经过验证的高通量验证方法的可用性，它确实为进一步分析提供了一个经济有效且合乎逻辑的起点。我们的项目将：目标 1) 对于每个 TCGA 癌症部位估计普遍的 CST，并预测在卵巢癌、结肠癌和肺癌患者中鉴定的 CST 的翻译状态。目标 2) 针对卵巢癌、结肠癌和肺癌，鉴定哪些预测的癌症选择性多肽含有可被 CD4 或 CD8 T 细胞识别的表位。目标 3) 通过确定从 III 期试验收集的样本中 T 细胞抑制途径被破坏后患者的免疫反应是否得到增强，前瞻性地验证肺癌抗原。

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.