Abstract
The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.
| Original language | English |
|---|---|
| Pages (from-to) | 201-218.e9 |
| Journal | Cancer Cell |
| Volume | 40 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 14 2022 |
| Externally published | Yes |
Keywords
- lactic acid
- liver metastasis
- MYC
- PD-1
- regulatory T cell
ASJC Scopus subject areas
- Oncology
- Cell Biology
- Cancer Research
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In: Cancer Cell, Vol. 40, No. 2, 14.02.2022, p. 201-218.e9.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments
AU - Kumagai, Shogo
AU - Koyama, Shohei
AU - Itahashi, Kota
AU - Tanegashima, Tokiyoshi
AU - Lin, Yi tzu
AU - Togashi, Yosuke
AU - Kamada, Takahiro
AU - Irie, Takuma
AU - Okumura, Genki
AU - Kono, Hidetoshi
AU - Ito, Daisuke
AU - Fujii, Rika
AU - Watanabe, Sho
AU - Sai, Atsuo
AU - Fukuoka, Shota
AU - Sugiyama, Eri
AU - Watanabe, Go
AU - Owari, Takuya
AU - Nishinakamura, Hitomi
AU - Sugiyama, Daisuke
AU - Maeda, Yuka
AU - Kawazoe, Akihito
AU - Yukami, Hiroki
AU - Chida, Keigo
AU - Ohara, Yuuki
AU - Yoshida, Tatsuya
AU - Shinno, Yuki
AU - Takeyasu, Yuki
AU - Shirasawa, Masayuki
AU - Nakama, Kenta
AU - Aokage, Keiju
AU - Suzuki, Jun
AU - Ishii, Genichiro
AU - Kuwata, Takeshi
AU - Sakamoto, Naoya
AU - Kawazu, Masahito
AU - Ueno, Toshihide
AU - Mori, Taisuke
AU - Yamazaki, Naoya
AU - Tsuboi, Masahiro
AU - Yatabe, Yasushi
AU - Kinoshita, Takahiro
AU - Doi, Toshihiko
AU - Shitara, Kohei
AU - Mano, Hiroyuki
AU - Nishikawa, Hiroyoshi
N1 - Funding Information: H.Nishikawa received research funding from Ono Pharmaceutical for this work, research funding and honoraria from Chugai Pharmaceutical , Bristol-Myers Squibb and MSD , honoraria from Ono Pharmaceutical , and research funding from Taiho Pharmaceutical , Daiichi-Sankyo , Kyowa Kirin , Zenyaku Kogyo, Oncolys BioPharma, Debiopharma, Asahi-Kasei, Sysmex, Fujifilm , SRL , Astellas Pharmaceutical, Sumitomo Dainippon Pharma, and BD Japan outside of this study. H.Nishikawa is the primary inventor on pending patents PCT /JP2020/0059919 belonging to the National Cancer Center Japan and BD Biosciences . S.Koyama received research funding from Ono Pharmaceutical and Bristol-Myers Squibb outside this study. Y.Togashi received research grants from KOTAI Biotechnologies Inc., Daiichi-Sankyo , Ono Pharmaceutical , Bristol-Myers Squibb , and honoraria from Ono Pharmaceutical , Bristol-Myers Squibb , AstraZeneca , Chugai Pharmaceutical , and MSD outside of this study. T.Yoshida received grants from Ono Pharmaceutical, AstraZeneca , AMGEN, Daiichi Sankyo, Bristol-Myers Squibb , MSD , Abbvie , and Takeda , and personal fees from Ono Pharmaceutical, AstraZeneca , Bristol-Myers Squibb , MSD , Takeda , Chugai , Novartis , Lilly , Taiho, Archer DX, and Roche outside of this study. K.S. received paid consulting or advisory roles for Astellas , Lilly , Bristol-Myers Squibb , Takeda , Pfizer , Ono, MSD , Taiho, Novartis , AbbVie , GlaxoSmithKline , Daiichi Sankyo, Amgen , and Boehringer Ingelheim; honoraria from Novartis , AbbVie , and Yakult; and research funding from Astellas , Lilly , Ono Pharmaceutical, Sumoitomo Dainippon, Daiichi Sankyo, Taiho, Chugai , MSD , Medi Science, and Eisai outside of this study. Y.S. received research funding from Ono Pharmaceutical and Janssen Pharma and personal fees from AstraZeneca , Chugai , and Pfizer . N.Y. received personal fees from Ono Pharmaceutical, grants from Bristol-Myers Squibb , grants and personal fees from Novartis Pharma K.K., outside the submitted work. All other authors declare no competing financial interests. Funding Information: This study was supported by Grants-in-Aid for Scientific Research (S grant no. 17H06162 to H.Nishikawa), Challenging Exploratory Research grant no. 16K15551 (to H.Nishikawa), C grant no. 21K07252 (to S.Koyama), JSPS KAKENHI grant no. 16H06279 (PAGS) (to S.Kumagai) and JSPS Research Fellowship no. 202101784 (to S.Kumagai)] from the Ministry of Education, Culture, Sports, Science and Technology of Japan ; by Projects for Cancer Research by Therapeutic Evolution (P-CREATE, no. 16cm0106301h000 1 to H.Nishikawa and no. 19cm0106335h0002 to S.Koyama), by the Development of Technology for Patient Stratification Biomarker Discovery grant (no. 19ae0101074s0401 to H.Nishikawa) from the Japan Agency for Medical Research and Development (AMED); by the National Cancer Center Research and Development Fund (nos. 28-A-7 and 31-A-7 to H.Nishikawa); by a Research Grant of the Princess Takamatsu Cancer Research Fund (to S.Koyama); by the Takeda Science Foundation (to Y.Togashi); by the Mochida Memorial Foundation (to Y.Togashi); by the Daiichi Sankyo Foundation (to Y.Togashi and S.Kumagai); by the Kowa Life Science Foundation (to Y.Togashi and S.Kumagai); by the MSD Life Science Foundation (to S.Kumagai); by SGH Foundation (to S.Kumagai); by the Ichiro Kanehara Foundation (to S.Kumagai); by the Yasuda Medical Foundation (to S.Kumagai); by the Suzuken Memorial Foundation (to S.Kumagai); by the Daiwa Securities Health Foundation (to S.Kumagai); by the Japan Research Foundation for Clinical Pharmacology (to S.Kumagai); by the Japanese Foundation for Multidisciplinary Treatment of Cancer (to S.Kumagai); by the Yokoyama Foundation For Clinical Pharmacology (to S.Kumagai) by the Japan Cancer Society (to S.Kumagai); by the Princess Takamatsu Cancer Research Fundation (to S.Kumagai); by the Hitachi Global Foundation (to S.Kumagai). This study was executed in part as a research program supported by Ono Pharmaceutical. Funding Information: DNA was extracted with the QIAmp DNA Mini Kit (QIAGEN) according to the manufacturer's instructions. Sequencing libraries were prepared for WES with a NEBNext Ultra DNA Library Prep Kit (New England BioLabs) according to the manufacturer's instructions. Adaptor-ligated samples were amplified with six PCR cycles. The amplified DNA fragments underwent enrichment for the exonic fragments using a SureSelect Human All Exon Kit v5 (Agilent Technologies). Massively parallel sequencing of the isolated fragments was performed with a HiSeq2500 platform (Illumina). Paired-end WES reads were independently aligned to the human reference genome (hg38) using BWA (Li and Durbin, 2009), Bowtie2 (http://bowtie-bio.sourceforge.net/bowtie2/index.shtml), and NovoAlign (http://www.novocraft.com/products/novoalign/). Somatic mutations were called using MuTect (http://www.broadinstitute.org/cancer/cga/mutect), SomaticIndelDetector (http://www.broadinstitute.org/cancer/cga/node/87), and VarScan (http://varscan.sourceforge.net). Mutations were discarded if (I) the read depth was < 20 or the variant allele frequency (VAF) was < 0.1, (II) they were supported by only one strand of the genome, or (III) they were present in the normal human genomes in either the 1000 Genomes Project dataset (http://www.internationalgenome.org/) or our in-house database. Gene mutations were annotated by SnpEff (http://snpeff.sourceforge.net). To detect MYC amplifications, genomic alterations were assessed using Oncomine™ Comprehensive Assay version 3 or Oncomine ™ Cancer Research Panel (Thermo Fisher Scientific, Waltham, MA).We thank Drs. Y. Takeuchi and Y. Koga, Ms. Y. Tada, T. Takaku, M. Nakai, K. Onagawa, M. Takemura, C. Haijima, M. Hoshino, K. Yoshida, M. Kikuchi, K. Katakura, Y. Nakamura, Y. Osada Y. Ohira, S. Yoshimatsu, and M. Ozawa, and Mr. T. Tahara for their technical assistance. In Memoriam: This article is dedicated to the memory of T. Kamada. This study was supported by Grants-in-Aid for Scientific Research (S grant no. 17H06162 to H.Nishikawa), Challenging Exploratory Research grant no. 16K15551 (to H.Nishikawa), C grant no. 21K07252 (to S.Koyama), JSPS KAKENHI grant no. 16H06279 (PAGS) (to S.Kumagai) and JSPS Research Fellowship no. 202101784 (to S.Kumagai)] from the Ministry of Education, Culture, Sports, Science and Technology of Japan; by Projects for Cancer Research by Therapeutic Evolution (P-CREATE, no. 16cm0106301h0001 to H.Nishikawa and no. 19cm0106335h0002 to S.Koyama), by the Development of Technology for Patient Stratification Biomarker Discovery grant (no.19ae0101074s0401 to H.Nishikawa) from the Japan Agency for Medical Research and Development (AMED); by the National Cancer Center Research and Development Fund (nos. 28-A-7 and 31-A-7 to H.Nishikawa); by a Research Grant of the Princess Takamatsu Cancer Research Fund (to S.Koyama); by the Takeda Science Foundation (to Y.Togashi); by the Mochida Memorial Foundation (to Y.Togashi); by the Daiichi Sankyo Foundation (to Y.Togashi and S.Kumagai); by the Kowa Life Science Foundation (to Y.Togashi and S.Kumagai); by the MSD Life Science Foundation (to S.Kumagai); by SGH Foundation (to S.Kumagai); by the Ichiro Kanehara Foundation (to S.Kumagai); by the Yasuda Medical Foundation (to S.Kumagai); by the Suzuken Memorial Foundation (to S.Kumagai); by the Daiwa Securities Health Foundation (to S.Kumagai); by the Japan Research Foundation for Clinical Pharmacology (to S.Kumagai); by the Japanese Foundation for Multidisciplinary Treatment of Cancer (to S.Kumagai); by the Yokoyama Foundation For Clinical Pharmacology (to S.Kumagai) by the Japan Cancer Society (to S.Kumagai); by the Princess Takamatsu Cancer Research Fundation (to S.Kumagai); by the Hitachi Global Foundation (to S.Kumagai). This study was executed in part as a research program supported by Ono Pharmaceutical. Conceptualization, S.Kumagai, S.Koyama, and H.Nishikawa; methodology, S.Kumagai, S.Koyama, K.I. Y.Togashi, and H.Nishikawa; investigation, S.Kumagai, T.Kamada. G.O. D.I. G.W. T.O. H.K. K.I. T.T. T.I. Y.L. R.F. S.W. A.S. S.F. E.S. H.Nishinakamura, D.S. Y.M. Y.O. M.K. and T.U.; collection of clinical specimens and data, A.K. H.Y. K.C. T.Yoshida, Y.S. Y.Takeyasu, M.S. K.N. K.A. N.S. T.M. G.I. T.Kuwata, N.Y. Y.O. M.T. Y.Y. T.Kinoshita, T.D. and K.S.; writing – original draft, S.Kumagai, S.Koyama, and H.Nishikawa; writing – review & editing, S.Kumagai, S.Koyama, H.M. and H.Nishikawa. H.Nishikawa received research funding from Ono Pharmaceutical for this work, research funding and honoraria from Chugai Pharmaceutical, Bristol-Myers Squibb and MSD, honoraria from Ono Pharmaceutical, and research funding from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Oncolys BioPharma, Debiopharma, Asahi-Kasei, Sysmex, Fujifilm, SRL, Astellas Pharmaceutical, Sumitomo Dainippon Pharma, and BD Japan outside of this study. H.Nishikawa is the primary inventor on pending patents PCT/JP2020/0059919 belonging to the National Cancer Center Japan and BD Biosciences. S.Koyama received research funding from Ono Pharmaceutical and Bristol-Myers Squibb outside this study. Y.Togashi received research grants from KOTAI Biotechnologies Inc. Daiichi-Sankyo, Ono Pharmaceutical, Bristol-Myers Squibb, and honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, Chugai Pharmaceutical, and MSD outside of this study. T.Yoshida received grants from Ono Pharmaceutical, AstraZeneca, AMGEN, Daiichi Sankyo, Bristol-Myers Squibb, MSD, Abbvie, and Takeda, and personal fees from Ono Pharmaceutical, AstraZeneca, Bristol-Myers Squibb, MSD, Takeda, Chugai, Novartis, Lilly, Taiho, Archer DX, and Roche outside of this study. K.S. received paid consulting or advisory roles for Astellas, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono, MSD, Taiho, Novartis, AbbVie, GlaxoSmithKline, Daiichi Sankyo, Amgen, and Boehringer Ingelheim; honoraria from Novartis, AbbVie, and Yakult; and research funding from Astellas, Lilly, Ono Pharmaceutical, Sumoitomo Dainippon, Daiichi Sankyo, Taiho, Chugai, MSD, Medi Science, and Eisai outside of this study. Y.S. received research funding from Ono Pharmaceutical and Janssen Pharma and personal fees from AstraZeneca, Chugai, and Pfizer. N.Y. received personal fees from Ono Pharmaceutical, grants from Bristol-Myers Squibb, grants and personal fees from Novartis Pharma K.K. outside the submitted work. All other authors declare no competing financial interests. Publisher Copyright: © 2022 Elsevier Inc.
PY - 2022/2/14
Y1 - 2022/2/14
N2 - The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.
AB - The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.
KW - lactic acid
KW - liver metastasis
KW - MYC
KW - PD-1
KW - regulatory T cell
UR - http://www.scopus.com/inward/record.url?scp=85124302491&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85124302491&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2022.01.001
DO - 10.1016/j.ccell.2022.01.001
M3 - Article
C2 - 35090594
AN - SCOPUS:85124302491
SN - 1535-6108
VL - 40
SP - 201-218.e9
JO - Cancer Cell
JF - Cancer Cell
IS - 2
ER -