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T细胞受体（TCR）序列的多样性令人难以置信，但有些在 人口；这些称为“公共TCR”（PTCR）。越来越意识到PTCR 有时可能发挥重要功能；例如，它们与长期控制 艾滋病病毒。我们发现了3个“ Special-Ptcrs”（SPTCR）是该提案的主题。正如我们所展示的 这些SPTCR在癌症患者的外周血中的存在高度相关 某些患者组的无进展生存和总体存活。在此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。 特定目的1：评估SPTCR在癌症患者中的SPTCR的预后价值 接受免疫疗法。我们假设SPTCR的存在将与改善有关 在我们机构治疗的肺癌，肾脏细胞癌和黑色素瘤患者中的临床结果， 以及在癌症免疫疗法试验网络试验中接受治疗的患者。我们假设 在接受检查点抑制剂治疗的患者中，这些SPTCR的预测价值最高。 特定目的2：确定SPTCR的特异性和免疫表型特征。使用 珠子和基于流动的细胞排序的组合我们将富集来自PBMC的SPTCR，以配对单个 细胞TCR和RNA测序分析以确定其表型和配对的αβ序列。使用 αβ配对序列，我们将确定它们的规格。通过识别正确的表型，其他 可以鉴定出癌症特异性PTCR作为生物标志物或治疗。