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

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 canc...

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Detalles Bibliográficos
Autores principales: Kamada, Takahiro, Togashi, Yosuke, Tay, Christopher, Ha, Danbee, Sasaki, Akinori, Nakamura, Yoshiaki, Sato, Eiichi, Fukuoka, Shota, Tada, Yasuko, Tanaka, Atsushi, Morikawa, Hiromasa, Kawazoe, Akihito, Kinoshita, Takahiro, Shitara, Kohei, Sakaguchi, Shimon, Nishikawa, Hiroyoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525547/
https://www.ncbi.nlm.nih.gov/pubmed/31028147
http://dx.doi.org/10.1073/pnas.1822001116
Descripción
Sumario: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 FoxP3(high)CD45RA(−)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.