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

预测癌症患者预后的特殊公共 T 细胞受体序列

• 批准号: 10577518
• 负责人: Seth M Pollack
• 金额: $ 22.44万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10577518
• 关键词: Adult; Amino Acid Sequence; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Awareness; Biological Markers; CD4 Positive T Lymphocytes; CD8B1 gene; CTAG1 gene; Cancer Patient; Cell Separation; Cells; Clinical; Clone Cells; Cytomegalovirus; Data; Gene Rearrangement; HIV; Human; Human Herpesvirus 4; Immune checkpoint inhibitor; Immunophenotyping; Immunotherapy; Individual; Institution; J-Chain Immunoglobulins; Life; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Melanoma Cell; Merkel cell carcinoma; Nucleotides; Outcome; PDL1 inhibitors; Patient-Focused Outcomes; Patients; Peptides; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Play; Population; Predictive Value; Process; Progression-Free Survivals; Proteins; Renal Cell Carcinoma; Risk Reduction; Specificity; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Viral; alpha-beta T-Cell Receptor; blood-based biomarker; cancer immunotherapy; cancer infiltrating T cells; cohort; complementarity-determining region 3; immunotherapy trials; improved; melanoma; neoantigens; novel; outcome prediction; pathogenic virus; peripheral blood; polypeptide; prognostic value; sarcoma; transcriptome sequencing; tumor

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.

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，但其中一些序列广泛存在于 人们越来越认识到这些被称为“公共 TCR”(pTCR)。 有时可能发挥重要作用；例如，它们与长期控制有关 正如我们所展示的，我们发现了 3 个“特殊 pTCR”（spTCR）。 癌症患者外周血中这些 spTCR 的存在与病情改善高度相关 在这个 R21 提案中，我们将研究某些进展组患者的自由生存率和总生存率。 彻底探究 spTCR 的预测能力并表征表达它们的细胞。 具体目标 1：评估 spTCR 在不同癌症患者群体中的预后价值 我们发现 spTCR 的存在与改善有关。 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。 这些 spTCR 的预测价值在接受检查点抑制剂治疗的患者中最高。 具体目标 2：使用 spTCR 鉴定特异性和免疫表型特征。 结合珠子和基于流的细胞分选，我们将从 PBMC 中富集 spTCR，用于配对单细胞 使用细胞 TCR 和 RNA 测序分析来确定其表型和配对的 αβ 序列。 αβ配对序列，我们将通过识别正确的表型，其他来确定它们的特异性。 癌症特异性 pTCR 可被鉴定用作生物标志物或治疗剂。