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- Title
Oncolytic virus-mediated reducing of myeloid-derived suppressor cells enhances the efficacy of PD-L1 blockade in gemcitabine-resistant pancreatic cancer.
- Authors
Kajiwara, Yoshinori; Tazawa, Hiroshi; Yamada, Motohiko; Kanaya, Nobuhiko; Fushimi, Takuro; Kikuchi, Satoru; Kuroda, Shinji; Ohara, Toshiaki; Noma, Kazuhiro; Yoshida, Ryuichi; Umeda, Yuzo; Urata, Yasuo; Kagawa, Shunsuke; Fujiwara, Toshiyoshi
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is often refractory to treatment with gemcitabine (GEM) and immune checkpoint inhibitors including anti-programmed cell death ligand 1 (PD-L1) antibody. However, the precise relationship between GEM-resistant PDAC and development of an immunosuppressive tumor microenvironment (TME) remains unclear. In this study, we investigated the immunosuppressive TME in parental and GEM-resistant PDAC tumors and assessed the therapeutic potential of combination therapy with the telomerase-specific replication-competent oncolytic adenovirus OBP-702, which induces tumor suppressor p53 protein and PD-L1 blockade against GEM-resistant PDAC tumors. Mouse PDAC cells (PAN02) and human PDAC cells (MIA PaCa-2, BxPC-3) were used to establish GEM-resistant PDAC lines. PD-L1 expression and the immunosuppressive TME were analyzed using parental and GEM-resistant PDAC cells. A cytokine array was used to investigate the underlying mechanism of immunosuppressive TME induction by GEM-resistant PAN02 cells. The GEM-resistant PAN02 tumor model was used to evaluate the antitumor effect of combination therapy with OBP-702 and PD-L1 blockade. GEM-resistant PDAC cells exhibited higher PD-L1 expression and produced higher granulocyte–macrophage colony-stimulating factor (GM-CSF) levels compared with parental cells, inducing an immunosuppressive TME and the accumulation of myeloid-derived suppressor cells (MDSCs). OBP-702 significantly inhibited GEM-resistant PAN02 tumor growth by suppressing GM-CSF-mediated MDSC accumulation. Moreover, combination treatment with OBP-702 significantly enhanced the antitumor efficacy of PD-L1 blockade against GEM-resistant PAN02 tumors. The present results suggest that combination therapy involving OBP-702 and PD-L1 blockade is a promising antitumor strategy for treating GEM-resistant PDAC with GM-CSF-induced immunosuppressive TME formation.
- Subjects
MYELOID-derived suppressor cells; PULMONARY alveolar proteinosis; TUMOR suppressor proteins; PROGRAMMED death-ligand 1; PANCREATIC cancer; GRANULOCYTE-macrophage colony-stimulating factor; ADENOVIRUS diseases; IPILIMUMAB; SOFOSBUVIR
- Publication
Cancer Immunology, Immunotherapy, 2023, Vol 72, Issue 5, p1285
- ISSN
0340-7004
- Publication type
Article
- DOI
10.1007/s00262-022-03334-x