Your browser doesn't support javascript.
loading
Antigen/HLA-agnostic strategies for Characterizing Tumor-responsive T cell receptors in PDAC patients via single-cell sequencing and autologous organoid application.
Wang, Xu; Dai, Zhengjie; Lin, Xuan; Zou, Xuan; Wang, Ruijie; Tasiheng, Yesboli; Yan, Yu; Ma, Mingjian; Chen, Yusheng; Cheng, He; Liu, Chen; Yu, Xianjun.
Afiliação
  • Wang X; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Precise Diagnosis and Treatment of Pancreatic Cancer, Shanghai Pancreatic Cancer Institute, Shan
  • Dai Z; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Precise Diagnosis and Treatment of Pancreatic Cancer, Shanghai Pancreatic Cancer Institute, Shan
  • Lin X; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Precise Diagnosis and Treatment of Pancreatic Cancer, Shanghai Pancreatic Cancer Institute, Shan
  • Zou X; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Precise Diagnosis and Treatment of Pancreatic Cancer, Shanghai Pancreatic Cancer Institute, Shan
  • Wang R; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Precise Diagnosis and Treatment of Pancreatic Cancer, Shanghai Pancreatic Cancer Institute, Shan
  • Tasiheng Y; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Precise Diagnosis and Treatment of Pancreatic Cancer, Shanghai Pancreatic Cancer Institute, Shan
  • Yan Y; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Precise Diagnosis and Treatment of Pancreatic Cancer, Shanghai Pancreatic Cancer Institute, Shan
  • Ma M; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Precise Diagnosis and Treatment of Pancreatic Cancer, Shanghai Pancreatic Cancer Institute, Shan
  • Chen Y; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Precise Diagnosis and Treatment of Pancreatic Cancer, Shanghai Pancreatic Cancer Institute, Shan
  • Cheng H; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Precise Diagnosis and Treatment of Pancreatic Cancer, Shanghai Pancreatic Cancer Institute, Shan
  • Liu C; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Precise Diagnosis and Treatment of Pancreatic Cancer, Shanghai Pancreatic Cancer Institute, Shan
  • Yu X; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Precise Diagnosis and Treatment of Pancreatic Cancer, Shanghai Pancreatic Cancer Institute, Shan
Cancer Lett ; 588: 216741, 2024 Apr 28.
Article em En | MEDLINE | ID: mdl-38395378
ABSTRACT
Characterization of tumor-responsive T cell receptors (TCRs) is a critical step in personalized TCR-T cell therapy, and remains challenging for pancreatic ductal adenocarcinoma (PDAC). Here we report a proof-of-concept study to identify and validate antitumor TCRs in two representative PDAC patients using ultradeep single-cell TCR/RNA sequencing and autologous organoids, and reveal the phenotypic dynamics of TCR repertoire in different T cell expansions from the same patient. We first performed comparative sequencing on freshly harvested peripheral blood mononuclear cells (PBMCs) and uncultured tumor infiltrating lymphocytes (TILs), followed by reactivity tests of TIL-enriched TCRs with autologous organoids, in which two tumor-responsive TCRs were successfully characterized and the corresponding TILs were mostly tissue-resident memory-like T cells, and partially expressed both naïve and exhausted T cell markers. For the PDAC patient without high-quality TILs, PBMCs were cultured with neoantigen peptide (KRASG12D), organoids, or anti-CD3 antibody in presence, and experienced extensive clonal expansions within ten days. All derived PBMCs were sequenced in parallel (>82,000 cells), and TCRs enriched in both peptide- and organoid-experienced, but not anti-CD3-treated CD8 T cells, were assessed for their reactivity to antigen-presenting cells (APCs) and organoids, in which three neoantigen-reactive TCRs were identified as tumor-responsive, and the corresponding T cells were characterized by mixed transcriptional signatures including but not limited to typical exhausted T cell markers. Together, our study revealed that the combination of ultradeep single-cell sequencing and organoid techniques enabled rapid characterization of tumor-responsive TCRs for developing practical personalized TCR-T therapy in an antigen/human leukocyte antigen (HLA)-agnostic manner.
Assuntos
Palavras-chave

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Receptores de Antígenos de Linfócitos T Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Receptores de Antígenos de Linfócitos T Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article