Oncolytic virus-mediated reducing of myeloid-derived suppressor cells enhances the efficacy of PD-L1 blockade in gemcitabine-resistant pancreatic cancer

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2023-05, Vol.72 (5), p.1285-1300
• Main 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
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Animals; Antitumor activity; Apoptosis; B7-H1 Antigen - metabolism; Cancer Research; Carcinoma, Pancreatic Ductal - metabolism; Cell death; Cell Line, Tumor; Colony-stimulating factor; Gemcitabine; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Humans; Immune checkpoint inhibitors; Immunology; Immunosuppressive Agents - therapeutic use; Medicine; Medicine & Public Health; Mice; Myeloid-Derived Suppressor Cells - metabolism; Oncology; Oncolysis; Oncolytic Viruses; p53 Protein; Pancreatic cancer; Pancreatic Neoplasms; PD-L1 protein; Suppressor cells; Tumor Microenvironment; Tumor suppressor genes; Tumors
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-022-03334-x

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.