Special Public T Cell Receptor Sequences that Predict Outcomes for Cancer Patients

项目摘要 尽管潜在的T细胞受体（TCR）序列具有令人难以置信的多样性，但其中一些广泛存在于 这些被称为“公共TCR”（pTCR）。越来越多的人意识到pTCR 有时可能发挥重要作用;例如，它们与长期控制 艾滋病。我们已经发现了3个“特殊pTCR”（spTCR），这是本提案的主题。正如我们所展示的， 这些spTCR在癌症患者外周血中的存在与改善的肿瘤细胞增殖高度相关。 某些患者组的无进展生存期和总生存期。在R21提案中，我们将 彻底询问spTCR的预测能力并表征表达它们的细胞。 具体目标1：评估spTCR在不同癌症患者队列中的预后价值 接受免疫治疗我们假设spTCR的存在将与改善的 在我们机构治疗的肺癌、肾细胞癌和黑色素瘤患者的临床结果， 以及接受癌症免疫治疗试验网络试验的患者。我们假设 这些spTCR的预测值在用检查点抑制剂治疗的患者中最高。 具体目标2：鉴定spTCR的特异性和免疫表型特征。使用 结合珠粒和基于流式细胞分选，我们将从PBMC富集spTCR，用于配对的单克隆抗体。 细胞TCR和RNA测序分析以确定它们的表型和配对的αβ序列。使用 αβ配对序列，我们将确定它们的特异性。通过识别正确的表型， 可以鉴定癌症特异性pTCR用作生物标记物或治疗剂。

Project Abstract Despite the incredible diversity of potential T cell receptor (TCR) sequences, some are found widely in the population; these are called "public TCRs" (pTCRs). There is a growing awareness that pTCRs may sometimes play important functions; for example, they have been linked to long term control of HIV. We have found 3 "special-pTCRs" (spTCRs) that are the subject of this proposal. As we show, the presence of these spTCRs in the peripheral blood of cancer patients is highly associated with improved progression free survival and overall survival in certain groups of patients. In this R21 proposal, we will thoroughly interrogate the predictive power of spTCRs and characterize the cells that express them. Specific Aim 1: To evaluate the prognostic value of spTCRs in diverse cohorts of cancer patients receiving immunotherapy. We hypothesize the presence of spTCRs will be associated with improved clinical outcomes in lung cancer, renal cell carcinoma and melanoma patients treated at our institution, as well as patients treated on Cancer Immunotherapy Trials Network trials. We hypothesize that the predictive value of these spTCRs will be highest in patients treated with checkpoint inhibitors. Specific Aim 2: To identify the specificity and immunophenotypic features of spTCRs. Using a combination of bead and flow-based cell sorting we will enrich spTCRs from PBMC for paired single- cell TCR and RNA sequencing analysis to determine their phenotype and paired αβ sequence. Using the αβ paired sequence, we will determine their specificities. By identifying the correct phenotype, other cancer specific pTCRs may be identified for use as biomarkers or therapeutics.