TY - JOUR
T1 - PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes
AU - Nagasaki, Joji
AU - Inozume, Takashi
AU - Sax, Nicolas
AU - Ariyasu, Ryo
AU - Ishikawa, Masakazu
AU - Yamashita, Kazuo
AU - Kawazu, Masahito
AU - Ueno, Toshihide
AU - Irie, Takuma
AU - Tanji, Etsuko
AU - Morinaga, Takao
AU - Honobe, Akiko
AU - Ohnuma, Takehiro
AU - Yoshino, Mitsuru
AU - Iwata, Takekazu
AU - Kawase, Katsushige
AU - Sasaki, Keita
AU - Hanazawa, Toyoyuki
AU - Kochin, Vitaly
AU - Kawamura, Tatsuyoshi
AU - Matsue, Hiroyuki
AU - Hino, Masayuki
AU - Mano, Hiroyuki
AU - Suzuki, Yutaka
AU - Nishikawa, Hiroyoshi
AU - Togashi, Yosuke
N1 - Funding Information:
We thank Ms. Noriko Sakurai for their technical assistance. This study was supported by Grants-in-Aid for Scientific Research (S grant no. 17H06162 to H.N. B grant no. 20H03694 to Y.T. and C grant no. 19K08744 to T.I.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Project for Cancer Research and Therapeutic Evolution (P-CREATE, nos. 16cm0106301h0002 to H.N. 18cm0106340h0001 to K.Y. and Y.T. 19cm0106502 to M.K. and 21cm0106383 to K.Y. and Y.T.); Practical Research for Innovative Cancer Control (19ck0106521h0001 to K.Y. and Y.T.); the Development of Technology for Patient Stratification Biomarker Discovery grant (no.19ae0101074s0401 to H.N.) from the Japan Agency for Medical Research and Development (AMED); the Fusion Oriented Research for disruptive Science and Technology (FOREST) (no. 21-211033868 to Y.T.) from Japan Science and Technology Agency (JST); the National Cancer Center Research and Development Fund (nos. 28-A-7 and 31-A-7 to H.N.); the Naito Foundation (to Y.T.); the Takeda Science Foundation (to Y.T.); the Mitsubishi Foundation (to Y.T.); the Tokyo Biochemical Research Foundation (to Y.T.); the Daiichi Sankyo Foundation (to Y.T.); the Foundation for Promotion of Cancer Research Japan (to Y.T.); the Mochida Memorial Foundation (to Y.T.); the Kanae Foundation for the Promotion of Medical Science (to Y.T.); the Yasuda Memorial Foundation for Medicine (to Y.T.); the MSD Life Science Foundation (to Y.T.); the Kowa Life Science Foundation (to Y.T.); the Senri Life Science Foundation (to Y.T.); and the Uehara Memorial Foundation (to Y.T.). This study was partially supported by KOTAI Biotechnologies Inc. Conceptualization, H.N. and Y.T.; methodology, J.N. T.I. N.S. R.A. M.I. K.Y. H.N. and Y.T.; investigation, J.N. T.I. N.S. R.A. M.I. K.Y. M.K. T.U. T.I. E.T. T.M. A.H. T.O. M.Y. T.I. K.K. K.S. T.H. V.K. T.K. H. Matsue, M.H. H. Mano, Y.S. H.N. and Y.T.; writing – original draft, J.N. T.I. N.S. K.Y. M.K. H.N. and Y.T.; writing – review & editing, J.N. T.I. N.S. K.Y. M.K. H.N. and Y.T.; funding acquisition, T.I. K.Y. M.K. H.N. and Y.T. N.S. M.I. and K.Y. are employees of KOTAI Biotechnologies Inc. T.I. received honoraria and research grants from Ono Pharmaceutical, Bristol-Myers Squibb, and MSD outside of this study. T.H. received a research grant from Ono Pharmaceutical outside of this study. H. Mano received a research grant from Ono Pharmaceutical outside of this study. H.N. received honoraria and research funding from Ono Pharmaceutical, Chugai Pharmaceutical, MSD and Bristol-Myers Squibb, and research funding from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Oncolys BioPharma, Debiopharm, Asahi-Kasei, Sysmex, Fujifilm, SRL, Astellas Pharmaceutical, Sumitomo Dainippon Pharma, and BD Japan outside of this study. Y.T. received a research grant from KOTAI Biotechnologies Inc. related to this study. Y.T. also received research grants and honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, and Daiichi-Sankyo, and honoraria from AstraZeneca, Chugai Pharmaceutical, and MSD outside of this study. All other authors declare no competing interests.
Funding Information:
This study was supported by Grants-in-Aid for Scientific Research (S grant no. 17H06162 to H.N., B grant no. 20H03694 to Y.T., and C grant no. 19K08744 to T.I.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan ; the Project for Cancer Research and Therapeutic Evolution ( P-CREATE , nos. 16cm0106301h0002 to H.N., 18cm0106340h0001 to K.Y. and Y.T., 19cm0106502 to M.K., and 21cm0106383 to K.Y. and Y.T.); Practical Research for Innovative Cancer Control ( 19ck0106521h0001 to K.Y. and Y.T.); the Development of Technology for Patient Stratification Biomarker Discovery grant (no. 19ae0101074s0401 to H.N.) from the Japan Agency for Medical Research and Development (AMED); the Fusion Oriented Research for disruptive Science and Technology (FOREST) (no. 21-211033868 to Y.T.) from Japan Science and Technology Agency (JST); the National Cancer Center Research and Development Fund (nos. 28-A-7 and 31-A-7 to H.N.); the Naito Foundation (to Y.T.); the Takeda Science Foundation (to Y.T.); the Mitsubishi Foundation (to Y.T.); the Tokyo Biochemical Research Foundation (to Y.T.); the Daiichi Sankyo Foundation (to Y.T.); the Foundation for Promotion of Cancer Research Japan (to Y.T.); the Mochida Memorial Foundation (to Y.T.); the Kanae Foundation for the Promotion of Medical Science (to Y.T.); the Yasuda Memorial Foundation for Medicine (to Y.T.); the MSD Life Science Foundation (to Y.T.); the Kowa Life Science Foundation (to Y.T.); the Senri Life Science Foundation (to Y.T.); and the Uehara Memorial Foundation (to Y.T.). This study was partially supported by KOTAI Biotechnologies Inc.
Funding Information:
N.S., M.I., and K.Y. are employees of KOTAI Biotechnologies Inc. T.I. received honoraria and research grants from Ono Pharmaceutical , Bristol-Myers Squibb , and MSD outside of this study. T.H. received a research grant from Ono Pharmaceutical outside of this study. H. Mano received a research grant from Ono Pharmaceutical outside of this study. H.N. received honoraria and research funding from Ono Pharmaceutical , Chugai Pharmaceutical , MSD and Bristol-Myers Squibb , and research funding from Taiho Pharmaceutical , Daiichi-Sankyo , Kyowa Kirin , Zenyaku Kogyo , Oncolys BioPharma , Debiopharm , Asahi-Kasei , Sysmex , Fujifilm , SRL , Astellas Pharmaceutical , Sumitomo Dainippon Pharma , and BD Japan outside of this study. Y.T. received a research grant from KOTAI Biotechnologies Inc . related to this study. Y.T. also received research grants and honoraria from Ono Pharmaceutical , Bristol-Myers Squibb , and Daiichi-Sankyo , and honoraria from AstraZeneca, Chugai Pharmaceutical, and MSD outside of this study. All other authors declare no competing interests.
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/2/1
Y1 - 2022/2/1
N2 - PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating T cells that directly attack tumor cells (tumor-specific T cells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander T cells. Here, using single-cell sequencing, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (Tex) or nonexhaustion signatures (Tnon-ex). Among skewed clonotypes, those in the Tex, but not those in the Tnon-ex, cluster respond to autologous tumor cell lines. After PD-1 blockade, non-preexisting tumor-specific clonotypes in the Tex cluster appear in the TME. Tumor-draining lymph nodes (TDLNs) without metastasis harbor a considerable number of such clonotypes, whereas these clonotypes are rarely detected in peripheral blood. We propose that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote infiltration of such Tex clonotypes, mainly from TDLNs.
AB - PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating T cells that directly attack tumor cells (tumor-specific T cells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander T cells. Here, using single-cell sequencing, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (Tex) or nonexhaustion signatures (Tnon-ex). Among skewed clonotypes, those in the Tex, but not those in the Tnon-ex, cluster respond to autologous tumor cell lines. After PD-1 blockade, non-preexisting tumor-specific clonotypes in the Tex cluster appear in the TME. Tumor-draining lymph nodes (TDLNs) without metastasis harbor a considerable number of such clonotypes, whereas these clonotypes are rarely detected in peripheral blood. We propose that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote infiltration of such Tex clonotypes, mainly from TDLNs.
KW - exhausted T cell
KW - neoantigen
KW - PD-1 blockade therapy
KW - single-cell RNA sequencing
KW - single-cell TCR sequencing
KW - tumor microenvironment
KW - tumor-draining lymph node
KW - tumor-specific T cell
UR - http://www.scopus.com/inward/record.url?scp=85123713048&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123713048&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2022.110331
DO - 10.1016/j.celrep.2022.110331
M3 - Article
C2 - 35108529
AN - SCOPUS:85123713048
SN - 2211-1247
VL - 38
JO - Cell Reports
JF - Cell Reports
IS - 5
M1 - 110331
ER -
