TY - JOUR
T1 - PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer
AU - Kamada, Takahiro
AU - Togashi, Yosuke
AU - Tay, Christopher
AU - Ha, Danbee
AU - Sasaki, Akinori
AU - Nakamura, Yoshiaki
AU - Sato, Eiichi
AU - Fukuoka, Shota
AU - Tada, Yasuko
AU - Tanaka, Atsushi
AU - Morikawa, Hiromasa
AU - Kawazoe, Akihito
AU - Kinoshita, Takahiro
AU - Shitara, Kohei
AU - Sakaguchi, Shimon
AU - Nishikawa, Hiroyoshi
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Ms. Tomoka Takaku, Miyuki Nakai, Konomi Onagawa, Megumi Takemura, Chie Haijima, Megumi Hoshino, Kumiko Yoshida, and Miho Ozawa for their technical assistance. This study was supported by Grants-in-Aid for Scientific Research [S Grant 17H06162 (to H.N.), Challenging Exploratory Research Grant 16K15551 (to H.N.), Young Scientists Grant 17J09900 (to Y. Togashi)], Japan Society for the Promotion of Science Research Fellow [Grants 17K18388 (to Y. Togashi) and 18J21161 (to T. Kamada)] and Grant-in-Aid for Specially Promoted Research [Grant 16H06295 (to S.S.)] from the Ministry of Education, Culture, Sports, Science and Technology of Japan, by the Project for Cancer Research, by Therapeutic Evolution [P-CREATE, Grants 16cm0106301h0002 (to H.N.), 18cm0106340h0001 (to Y. Togashi), and 18cm0106303h0003 (to S.S.)] Core Research for Evolutional Science and Technology [CREST, Grant 17gm0410016h0006 (to S.S.)], and Leading Advanced Projects for medical innovation [LEAP, Grant 18gm0010005h0001 (to
Funding Information:
S.S.)] from Japan Agency for Medical Research and Development (AMED), by the National Cancer Center Research and Development Fund [no. 28-A-7 (to H.N.)], by the Naito Foundation (to Y. Togashi and H.N.), by the Takeda Foundation (to Y. Togashi), by the Kobayashi Foundation for Cancer Research (to Y. Togashi),
Funding Information:
by the Novartis Research Grant (to Y. Togashi), by the Bristol-Myers Squibb Research Grant (to Y. Togashi), and by the Sagawa Holdings Foundation (to Y. Togashi). The analysis of immune status was executed in part as a research program supported by Ono Pharmaceutical Co., Ltd.
Funding Information:
Conflict of interest statement: The Sponsor declares a conflict of interest. Y. Togashi has received honoraria and grants from Ono Pharmaceutical as to this work, honoraria and grants from Bristol-Myers Squibb and AstraZeneca, and honoraria from Chugai Pharmaceutical and Merck Sharp & Dohme (MSD) outside of this study. K.S. received honoraria and grants from Ono Pharmaceutical and Bristol-Myers Squibb and grants from MSD outside of this study. H.N. received honoraria and grants from Ono Pharmaceutical as to this work, honoraria and grants from Bristol-Myers Squibb and Chugai Pharmaceutical, and grants from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa-Hakko Kirin, Zenyaku Kogyo, Astellas Pharmaceutical, Sysmex, and BD Japan outside of this study. Other authors declare no competing financial interests. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). 1T. Kamada, Y. Togashi, and C.T. contributed equally to this work. 2To whom correspondence may be addressed. Email: shimon@ifrec.osaka-u.ac.jp or hnishika@ncc.go.jp. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 1073/pnas.1822001116/-/DCSupplemental. Published online April 26, 2019.
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/5/14
Y1 - 2019/5/14
N2 - 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.
AB - 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.
KW - Hyperprogressive disease
KW - Immune-checkpoint blockade
KW - PD-1
KW - Regulatory T cells
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U2 - 10.1073/pnas.1822001116
DO - 10.1073/pnas.1822001116
M3 - Article
C2 - 31028147
AN - SCOPUS:85065707575
VL - 116
SP - 9999
EP - 10008
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 20
ER -