Non-conventional Inhibitory CD4+Foxp3-PD-1hi T Cells as a Biomarker of Immune Checkpoint Blockade Activity. Academic Article uri icon



  • A significant proportion of cancer patients do not respond to immune checkpoint blockade. To better understand the molecular mechanisms underlying these treatments, we explored the role of CD4+Foxp3- T cells expressing PD-1 (4PD1hi) and observed that 4PD1hi accumulate intratumorally as a function of tumor burden. Interestingly, CTLA-4 blockade promotes intratumoral and peripheral 4PD1hi increases in a dose-dependent manner, while combination with PD-1 blockade mitigates this effect and improves anti-tumor activity. We found that lack of effective 4PD1hi reduction after anti-PD-1 correlates with poor prognosis. Mechanistically, we provide evidence that mouse and human circulating and intra-tumor 4PD1hi inhibit T cell functions in a PD-1/PD-L1 dependent fashion and resemble follicular helper T cell (TFH)-like cells. Accordingly, anti-CTLA-4 activity is improved in TFH deficient mice.

publication date

  • June 11, 2018



  • CD4-Positive T-Lymphocytes
  • Forkhead Transcription Factors
  • Neoplasms
  • Programmed Cell Death 1 Receptor


PubMed Central ID

  • PMC6648657

Scopus Document Identifier

  • 85047523663

Digital Object Identifier (DOI)

  • 10.1016/j.ccell.2018.05.009

PubMed ID

  • 29894689

Additional Document Info


  • 33


  • 6