Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All...
  • Videos
  • Collections
    • Recently published
    • Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Transfers
  • Current issue
  • Past issues
  • By specialty
  • Contact
  • Recently published
  • Technical Advances
  • Clinical Medicine
  • Editorials
  • Top read articles
Multiple cancer-specific antigens are targeted by a chimeric antigen receptor on a single cancer cell
Yanran He, … , David M. Kranz, Hans Schreiber
Yanran He, … , David M. Kranz, Hans Schreiber
Published November 27, 2019; First published November 1, 2019
Citation Information: JCI Insight. 2019;4(21):e130416. https://doi.org/10.1172/jci.insight.130416.
View: Text | PDF | Corrigendum
Categories: Research Article Immunology

Multiple cancer-specific antigens are targeted by a chimeric antigen receptor on a single cancer cell

  • Text
  • PDF
Abstract

Human cancer cells were eradicated by adoptive transfer of T cells transduced with a chimeric antigen receptor (CAR) made from an antibody (237Ab) that is highly specific for the murine Tn-glycosylated podoplanin (Tn-PDPN). The objectives were to determine the specificity of these CAR-transduced T (CART) cells and the mechanism for the absence of relapse. We show that although the 237Ab bound only to cell lines expressing murine Tn-PDPN, the 237Ab-derived 237CART cells lysed multiple different human and murine cancers not predicted by the 237Ab binding. Nevertheless, the 237CART cell reactivities remained cancer specific because all recognitions were dependent on the Tn glycosylation that resulted from COSMC mutations that were not present in normal tissues. While Tn was required for the recognition by 237CART, Tn alone was not sufficient for 237CART cell activation. Activation of 237CART cells required peptide backbone recognition but tolerated substitutions of up to 5 of the 7 amino acid residues in the motif recognized by 237Ab. Together, these findings demonstrate what we believe is a new principle whereby simultaneous recognition of multiple independent Tn-glycopeptide antigens on a cancer cell makes tumor escape due to antigen loss unlikely.

Authors

Yanran He, Karin Schreiber, Steven P. Wolf, Frank Wen, Catharina Steentoft, Jonathan Zerweck, Madeline Steiner, Preeti Sharma, H. Michael Shepard, Avery Posey, Carl H. June, Ulla Mandel, Henrik Clausen, Matthias Leisegang, Stephen C. Meredith, David M. Kranz, Hans Schreiber

×

Figure 4

The 237CART recognition of COSMC-mutant cancers prefers, but does not require, Tn-PDPN expression.

Options: View larger image (or click on image) Download as PowerPoint
The 237CART recognition of COSMC-mutant cancers prefers, but does not re...
The COSMC-mutant or –wild-type variants with or without murine PDPN expression of each parental cell line were generated as described in the Methods. The activation of 237CART cells upon recognition of different cell lines was determined by target lysis in a 4-hour 51Cr release assay (upper panels), and by IFN-γ release into the medium after a 24-hour coincubation of 237CART with the target cells (lower panels). Mean ± SEM, n = 3 from 3 independent experiments. Significance of the difference between 2 groups as indicated was determined by 2-tailed Student’s t test. ns indicates P > 0.05; *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.
Follow JCI Insight:
Copyright © 2019 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts