PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer

Proc Natl Acad Sci U S A. 2019 May 14;116(20):9999-10008. doi: 10.1073/pnas.1822001116. Epub 2019 Apr 26.


PD-1 blockade is a cancer immunotherapy effective in various types of cancer. In a fraction of treated patients, however, it causes rapid cancer progression called hyperprogressive disease (HPD). With our observation of HPD in ∼10% of anti-PD-1 monoclonal antibody (mAb)-treated advanced gastric cancer (GC) patients, we explored how anti-PD-1 mAb caused HPD in these patients and how HPD could be treated and prevented. In the majority of GC patients, tumor-infiltrating FoxP3highCD45RA-CD4+ T cells [effector Treg (eTreg) cells], which were abundant and highly suppressive in tumors, expressed PD-1 at equivalent levels as tumor-infiltrating CD4+ or CD8+ effector/memory T cells and at much higher levels than circulating eTreg cells. Comparison of GC tissue samples before and after anti-PD-1 mAb therapy revealed that the treatment markedly increased tumor-infiltrating proliferative (Ki67+) eTreg cells in HPD patients, contrasting with their reduction in non-HPD patients. Functionally, circulating and tumor-infiltrating PD-1+ eTreg cells were highly activated, showing higher expression of CTLA-4 than PD-1- eTreg cells. PD-1 blockade significantly enhanced in vitro Treg cell suppressive activity. Similarly, in mice, genetic ablation or antibody-mediated blockade of PD-1 in Treg cells increased their proliferation and suppression of antitumor immune responses. Taken together, PD-1 blockade may facilitate the proliferation of highly suppressive PD-1+ eTreg cells in HPDs, resulting in inhibition of antitumor immunity. The presence of actively proliferating PD-1+ eTreg cells in tumors is therefore a reliable marker for HPD. Depletion of eTreg cells in tumor tissues would be effective in treating and preventing HPD in PD-1 blockade cancer immunotherapy.

Keywords: PD-1; hyperprogressive disease; immune-checkpoint blockade; regulatory T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Antineoplastic Agents, Immunological / adverse effects*
  • CTLA-4 Antigen / metabolism
  • Disease Progression
  • Humans
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Male
  • Mice
  • Nivolumab / adverse effects*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / immunology*
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / metabolism


  • Antineoplastic Agents, Immunological
  • CTLA-4 Antigen
  • Programmed Cell Death 1 Receptor
  • Nivolumab