Detecting Tumor Antigen-Specific T Cells via Interaction-Dependent Fucosyl-Biotinylation

Cell. 2020 Nov 12;183(4):1117-1133.e19. doi: 10.1016/j.cell.2020.09.048. Epub 2020 Oct 22.

Abstract

Re-activation and clonal expansion of tumor-specific antigen (TSA)-reactive T cells are critical to the success of checkpoint blockade and adoptive transfer of tumor-infiltrating lymphocyte (TIL)-based therapies. There are no reliable markers to specifically identify the repertoire of TSA-reactive T cells due to their heterogeneous composition. We introduce FucoID as a general platform to detect endogenous antigen-specific T cells for studying their biology. Through this interaction-dependent labeling approach, intratumoral TSA-reactive CD4+, CD8+ T cells, and TSA-suppressive CD4+ T cells can be detected and separated from bystander T cells based on their cell-surface enzymatic fucosyl-biotinylation. Compared to bystander TILs, TSA-reactive TILs possess a distinct T cell receptor (TCR) repertoire and unique gene features. Although exhibiting a dysfunctional phenotype, TSA-reactive CD8+ TILs possess substantial capabilities of proliferation and tumor-specific killing. Featuring genetic manipulation-free procedures and a quick turnover cycle, FucoID should have the potential of accelerating the pace of personalized cancer treatment.

Keywords: TCR sequencing; antigen-specific T cell; bystander T cell; cancer; cell-cell interaction; glycosylation; immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Animals
  • Antigens, Neoplasm / metabolism*
  • Biomarkers, Tumor / metabolism
  • Biotinylation
  • Bystander Effect / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Communication*
  • Cell Membrane / metabolism
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Female
  • Fucose / metabolism*
  • Fucosyltransferases / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Helicobacter pylori / enzymology
  • Humans
  • Immunity
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Mice, Inbred C57BL
  • Peptides / chemistry
  • Phenotype
  • Programmed Cell Death 1 Receptor / metabolism
  • Spleen / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology*

Substances

  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • Peptides
  • Programmed Cell Death 1 Receptor
  • Fucose
  • Fucosyltransferases