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

Takahiro Kamada, Yosuke Togashi, Christopher Tay, Danbee Ha, Akinori Sasaki, Yoshiaki Nakamura, Eiichi Sato, Shota Fukuoka, Yasuko Tada, Atsushi Tanaka, Hiromasa Morikawa, Akihito Kawazoe, Takahiro Kinoshita, Kohei Shitara, Shimon Sakaguchi, Hiroyoshi Nishikawa

Research output: Contribution to journalArticlepeer-review

604 Citations (Scopus)


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 FoxP3highCD45RACD4+ 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.

Original languageEnglish
Pages (from-to)9999-10008
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number20
Publication statusPublished - May 14 2019
Externally publishedYes


  • Hyperprogressive disease
  • Immune-checkpoint blockade
  • PD-1
  • Regulatory T cells

ASJC Scopus subject areas

  • General


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