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

Abstract

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.

• Authors: Young Min Chung, Pragya P Khan, Hong Wang, Wen-Bin Tsai, Yanli Qiao, Bo Yu, James W Larrick, Mickey C-T Hu
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 9 Issue 12 (12 2021) ISSN: 2051-1426 [Electronic] England
• PMID: 34887262 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 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.

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• FOXO3 protein, human
• Forkhead Box Protein O3
• Immune Checkpoint Inhibitors
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Topoisomerase I Inhibitors
• Irinotecan

Topics

• Animals
• Apoptosis
• B7-H1 Antigen (antagonists & inhibitors, metabolism)
• Breast Neoplasms (drug therapy, immunology, metabolism, pathology)
• CD8-Positive T-Lymphocytes (immunology)
• Carcinoma, Hepatocellular (drug therapy, immunology, metabolism, pathology)
• Cell Proliferation
• Female
• Forkhead Box Protein O3 (genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immune Checkpoint Inhibitors (pharmacology)
• Immunotherapy
• Irinotecan (pharmacology)
• Killer Cells, Natural (immunology)
• Liver Neoplasms (drug therapy, immunology, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Ovarian Neoplasms (drug therapy, immunology, metabolism, pathology)
• Prognosis
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Topoisomerase I Inhibitors (pharmacology)
• Tumor Cells, Cultured
• Tumor Microenvironment