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天然适合于开发为几乎任何治疗方式的靶标，因为它们具有靶向而不对正常组织产生不利影响的潜力。我们假设，普遍的癌症选择性转录本（CST）的翻译产物首先确定的TCGA可能是丰富的新抗原，选择性地提出的MHC I类或II类分子的恶性细胞的表面上，因此代表有吸引力的免疫治疗的目标。最有希望的靶点可以通过计算方法来鉴定，该方法将TCGA RNA序列数据与良好策划的数据资源整合，以分析体细胞组织，并与有价值的本地数据资源整合，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的每一种中鉴定出大量的CST，这些CST（i）在来自多个不同患者的癌组织中表达，（ii）在未转化的成人体细胞组织中明显缺失，（iii）来源于实体瘤的恶性细胞组分，并且（iv）具有预防活性。我们鉴定的CST包括以前已显示产生可引发CD8+ T细胞免疫应答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发现。虽然在癌症组织样品中鉴定明显的癌症选择性转录物并不能保证新抗原的存在，但考虑到经证实的高通量验证方法的可用性，它确实为进一步分析提供了具有成本效益和逻辑起点。目的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。目的2）针对卵巢癌、结肠癌、肺癌，鉴定预测的癌症选择性多肽中哪些具有被CD4+或CD8+ T细胞识别的表位。目的3）通过确定在从III期试验收集的样品中T细胞抑制途径破坏后患者免疫应答是否增强来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.