Transient Depletion of CD4+ Cells Induces Remodeling of the TCR Repertoire in Gastrointestinal Cancer

Cancer Immunol Res. 2021 Jun;9(6):624-636. doi: 10.1158/2326-6066.CIR-20-0989. Epub 2021 Mar 5.


Antibody-mediated transient depletion of CD4+ cells enhances the expansion of tumor-reactive CD8+ T cells and exhibits robust antitumor effects in preclinical and clinical studies. To investigate the clonal T-cell responses following transient CD4+ cell depletion in patients with cancer, we conducted a temporal analysis of the T-cell receptor (TCR) repertoire in the first-in-human clinical trial of IT1208, a defucosylated humanized monoclonal anti-CD4. Transient depletion of CD4+ cells promoted replacement of T-cell clones among CD4+ and CD8+ T cells in the blood. This replacement of the TCR repertoire was associated with the extent of CD4+ T-cell depletion and an increase in CD8+ T-cell count in the blood. Next, we focused on T-cell clones overlapping between the blood and tumor in order to track tumor-associated T-cell clones in the blood. The total frequency of blood-tumor overlapping clones tended to increase in patients receiving a depleting dose of anti-CD4, which was accompanied by the replacement of overlapping clones. The greater expansion of CD8+ overlapping clones was commonly observed in the patients who achieved tumor shrinkage. These results suggested that the clonal replacement of the TCR repertoire induced by transient CD4+ cell depletion was accompanied by the expansion of tumor-reactive T-cell clones that mediated antitumor responses. Our findings propose beneficial remodeling of the TCR repertoire following transient CD4+ cell depletion and provide novel insight into the antitumor effects of monoclonal anti-CD4 treatment in patients with cancer.See related Spotlight on p. 601.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antineoplastic Agents, Immunological / pharmacology*
  • CD4 Antigens / antagonists & inhibitors*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / drug effects
  • Drug Administration Schedule
  • Female
  • Gastrointestinal Neoplasms / drug therapy*
  • Gastrointestinal Neoplasms / immunology
  • Humans
  • Male
  • Middle Aged
  • Receptors, Antigen, T-Cell / genetics*
  • Treatment Outcome


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • CD4 Antigens
  • Receptors, Antigen, T-Cell