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

• Published in: Journal for immunotherapy of cancer Vol. 9; no. 12; p. e002772
• Main Authors: Chung, Young Min, Khan, Pragya P, Wang, Hong, Tsai, Wen-Bin, Qiao, Yanli, Yu, Bo, Larrick, James W, Hu, Mickey C-T
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.12.2021; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Original research
• Subjects: Animals; Antibodies; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - metabolism; Breast Neoplasms - drug therapy; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer therapies; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; CD8-positive T-lymphocytes; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; Clinical/Translational Cancer Immunotherapy; Cloning; combined modality therapy; Cytotoxicity; Drug dosages; Female; Forkhead Box Protein O3 - genetics; Forkhead Box Protein O3 - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immune Checkpoint Inhibitors - pharmacology; immunomodulation; Immunotherapy; Irinotecan - pharmacology; Killer Cells, Natural - immunology; Laboratories; Ligands; Liver Neoplasms - drug therapy; Liver Neoplasms - immunology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Lymphocytes; Mice; Mice, Inbred C57BL; natural killer T-cells; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - immunology; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Prognosis; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Proteins; Topoisomerase I Inhibitors - pharmacology; Tumor Cells, Cultured; Tumor Microenvironment; Tumors; United States > US; Maryland; Pennsylvania; immunomodulation; combined modality therapy; CD8-positive T-lymphocytes; natural killer T-cells; immunotherapy
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2021-002772

BackgroundStimulating 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.MethodsWe 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.ResultsWe 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.ConclusionWe 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.