Cargando…

Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3

BACKGROUND: Stimulating antitumor immunity by blocking programmed death-1 (PD-1) or its ligand (programmed death-ligand 1 (PD-L1) is a promising antitumor therapy. However, numerous patients respond poorly to PD-1/PD-L1 blockade. Unresponsiveness to immune-checkpoint blockade (ICB) can cast signific...

Descripción completa

Detalles Bibliográficos
Autores principales: Chung, Young Min, Khan, Pragya P, Wang, Hong, Tsai, Wen-Bin, Qiao, Yanli, Yu, Bo, Larrick, James W, Hu, Mickey C-T
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663085/
https://www.ncbi.nlm.nih.gov/pubmed/34887262
http://dx.doi.org/10.1136/jitc-2021-002772
_version_ 1784613561524289536
author Chung, Young Min
Khan, Pragya P
Wang, Hong
Tsai, Wen-Bin
Qiao, Yanli
Yu, Bo
Larrick, James W
Hu, Mickey C-T
author_facet Chung, Young Min
Khan, Pragya P
Wang, Hong
Tsai, Wen-Bin
Qiao, Yanli
Yu, Bo
Larrick, James W
Hu, Mickey C-T
author_sort Chung, Young Min
collection PubMed
description BACKGROUND: Stimulating antitumor immunity by blocking programmed death-1 (PD-1) or its ligand (programmed death-ligand 1 (PD-L1) is a promising antitumor therapy. However, numerous patients respond poorly to PD-1/PD-L1 blockade. Unresponsiveness to immune-checkpoint blockade (ICB) can cast significant challenges to the therapeutic options for patients with hard-to-treat tumors. There is an unmet clinical need to establish new therapeutic approaches for mitigating ICB unresponsiveness in patients. In this study, we investigated the efficacy and role of low-dose antineoplastic agent SN-38 or metformin in sensitizing unresponsive tumors to respond to ICB therapy. METHODS: We assessed the significant pathological relationships between PD-L1 and FOXO3 expression and between PD-L1 and c-Myc or STAT3 expression in patients with various tumors. We determined the efficacy of low-dose SN-38 or metformin in sensitizing unresponsive tumors to respond to anti-PD-1 therapy in a syngeneic tumor system. We deciphered novel therapeutic mechanisms underlying the SN-38 and anti-PD-1 therapy-mediated engagement of natural killer (NK) or CD8+ T cells to infiltrate tumors and boost antitumor immunity. RESULTS: We showed that PD-L1 protein level was inversely associated with FOXO3 protein level in patients with ovarian, breast, and hepatocellular tumors. Low-dose SN-38 or metformin abrogated PD-L1 protein expression, promoted FOXO3 protein level, and significantly increased the animal survival rate in syngeneic mouse tumor models. SN-38 or metformin sensitized unresponsive tumors responding to anti-PD-1 therapy by engaging NK or CD8+ T cells to infiltrate the tumor microenvironment (TME) and secret interferon-γ and granzyme B to kill tumors. SN-38 suppressed the levels of c-Myc and STAT3 proteins, which controlled PD-L1 expression. FOXO3 was essential for SN38-mediated PD-L1 suppression. The expression of PD-L1 was compellingly linked to that of c-Myc or STAT3 in patients with the indicated tumors. CONCLUSION: We show that SN-38 or metformin can boost antitumor immunity in the TME by inhibiting c-Myc and STAT3 through FOXO3 activation. These results may provide novel insight into ameliorating patient response to overarching immunotherapy for tumors.
format Online
Article
Text
id pubmed-8663085
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher BMJ Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-86630852021-12-28 Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3 Chung, Young Min Khan, Pragya P Wang, Hong Tsai, Wen-Bin Qiao, Yanli Yu, Bo Larrick, James W Hu, Mickey C-T J Immunother Cancer Clinical/Translational Cancer Immunotherapy BACKGROUND: Stimulating antitumor immunity by blocking programmed death-1 (PD-1) or its ligand (programmed death-ligand 1 (PD-L1) is a promising antitumor therapy. However, numerous patients respond poorly to PD-1/PD-L1 blockade. Unresponsiveness to immune-checkpoint blockade (ICB) can cast significant challenges to the therapeutic options for patients with hard-to-treat tumors. There is an unmet clinical need to establish new therapeutic approaches for mitigating ICB unresponsiveness in patients. In this study, we investigated the efficacy and role of low-dose antineoplastic agent SN-38 or metformin in sensitizing unresponsive tumors to respond to ICB therapy. METHODS: We assessed the significant pathological relationships between PD-L1 and FOXO3 expression and between PD-L1 and c-Myc or STAT3 expression in patients with various tumors. We determined the efficacy of low-dose SN-38 or metformin in sensitizing unresponsive tumors to respond to anti-PD-1 therapy in a syngeneic tumor system. We deciphered novel therapeutic mechanisms underlying the SN-38 and anti-PD-1 therapy-mediated engagement of natural killer (NK) or CD8+ T cells to infiltrate tumors and boost antitumor immunity. RESULTS: We showed that PD-L1 protein level was inversely associated with FOXO3 protein level in patients with ovarian, breast, and hepatocellular tumors. Low-dose SN-38 or metformin abrogated PD-L1 protein expression, promoted FOXO3 protein level, and significantly increased the animal survival rate in syngeneic mouse tumor models. SN-38 or metformin sensitized unresponsive tumors responding to anti-PD-1 therapy by engaging NK or CD8+ T cells to infiltrate the tumor microenvironment (TME) and secret interferon-γ and granzyme B to kill tumors. SN-38 suppressed the levels of c-Myc and STAT3 proteins, which controlled PD-L1 expression. FOXO3 was essential for SN38-mediated PD-L1 suppression. The expression of PD-L1 was compellingly linked to that of c-Myc or STAT3 in patients with the indicated tumors. CONCLUSION: We show that SN-38 or metformin can boost antitumor immunity in the TME by inhibiting c-Myc and STAT3 through FOXO3 activation. These results may provide novel insight into ameliorating patient response to overarching immunotherapy for tumors. BMJ Publishing Group 2021-12-08 /pmc/articles/PMC8663085/ /pubmed/34887262 http://dx.doi.org/10.1136/jitc-2021-002772 Text en © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Clinical/Translational Cancer Immunotherapy
Chung, Young Min
Khan, Pragya P
Wang, Hong
Tsai, Wen-Bin
Qiao, Yanli
Yu, Bo
Larrick, James W
Hu, Mickey C-T
Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3
title Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3
title_full Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3
title_fullStr Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3
title_full_unstemmed Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3
title_short Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3
title_sort sensitizing tumors to anti-pd-1 therapy by promoting nk and cd8+ t cells via pharmacological activation of foxo3
topic Clinical/Translational Cancer Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663085/
https://www.ncbi.nlm.nih.gov/pubmed/34887262
http://dx.doi.org/10.1136/jitc-2021-002772
work_keys_str_mv AT chungyoungmin sensitizingtumorstoantipd1therapybypromotingnkandcd8tcellsviapharmacologicalactivationoffoxo3
AT khanpragyap sensitizingtumorstoantipd1therapybypromotingnkandcd8tcellsviapharmacologicalactivationoffoxo3
AT wanghong sensitizingtumorstoantipd1therapybypromotingnkandcd8tcellsviapharmacologicalactivationoffoxo3
AT tsaiwenbin sensitizingtumorstoantipd1therapybypromotingnkandcd8tcellsviapharmacologicalactivationoffoxo3
AT qiaoyanli sensitizingtumorstoantipd1therapybypromotingnkandcd8tcellsviapharmacologicalactivationoffoxo3
AT yubo sensitizingtumorstoantipd1therapybypromotingnkandcd8tcellsviapharmacologicalactivationoffoxo3
AT larrickjamesw sensitizingtumorstoantipd1therapybypromotingnkandcd8tcellsviapharmacologicalactivationoffoxo3
AT humickeyct sensitizingtumorstoantipd1therapybypromotingnkandcd8tcellsviapharmacologicalactivationoffoxo3