Combined therapeutic effect of YHO-1701 with PD-1 blockade is dependent on natural killer cell activity in syngeneic mouse models.

Abstract

The signal transducer and activator of transcription 3 (STAT3) signaling pathway is a key mediator of cancer cell proliferation, survival, and invasion. We discovered YHO-1701 as a small molecule inhibitor of STAT3 dimerization and demonstrated its potent anti-tumor activity using xenograft mouse models as monotherapy and combination therapy with molecular targeted drugs. STAT3 is also associated with cancer immune tolerance; therefore, we used the female CT26 syngeneic mouse model to examine the effect of combining YHO-1701 administration with PD-1/PD-L1 blockade. Pretreatment of the mice with YHO-1701 before starting anti-PD-1 antibody administration resulted in a significant therapeutic effect. In addition, the effect of monotherapy and combination treatment with YHO-1701 was significantly abolished by depleting natural killer (NK) cell activity. YHO-1701 was also found to restore the activity of mouse NK cells under inhibitory conditions in vitro. Furthermore, this combination therapy significantly inhibited tumor growth in an immunotherapy-resistant model of murine CMS5a fibrosarcoma. These results suggest that the combination of YHO-1701 with PD-1/PD-L1 blockade might be a new candidate for cancer immunotherapy involving the enhancement of NK cell activity in the tumor microenvironment.

• Authors: Hiroyuki Takahashi, Nao Miyoshi, Hisashi Murakami, Yuta Okamura, Naohisa Ogo, Akimitsu Takagi, Daisuke Muraoka, Akira Asai
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 72 Issue 7 Pg. 2473-2482 (Jul 2023) ISSN: 1432-0851 [Electronic] Germany
• PMID: 37017695 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• YHO-1701
• Stat3 protein, mouse
• Pdcd1 protein, mouse
• STAT3 Transcription Factor
• Programmed Cell Death 1 Receptor
• Quinolines
• Antibodies

Topics

• Animals
• Mice
• Mice, Inbred BALB C
• Fibrosarcoma (drug therapy)
• Killer Cells, Natural (drug effects)
• STAT3 Transcription Factor (metabolism)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Quinolines (administration & dosage)
• Antibodies (administration & dosage)
• Transplantation, Isogeneic