Impact of combination therapy with anti-PD-1 blockade and a STAT3 inhibitor on the tumor-infiltrating lymphocyte status

• Published in: Immunology letters Vol. 216; pp. 43 - 50
• Main Authors: Ashizawa, Tadashi, Iizuka, Akira, Maeda, Chie, Tanaka, Emiko, Kondou, Ryota, Miyata, Haruo, Sugino, Takashi, Kawata, Takuya, Deguchi, Shoichi, Mitsuya, Koichi, Hayashi, Nakamasa, Asai, Akira, Ito, Mamoru, Yamaguchi, Ken, Akiyama, Yasuto
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2019
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cell Line, Tumor; Drug Interactions; Exhaustion marker; Genes, MHC Class I - genetics; Genes, MHC Class II - genetics; Humanized NOG-MHC dKO mouse; Humans; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - transplantation; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Mice; Mice, Knockout; Oxadiazoles - pharmacology; Oxadiazoles - therapeutic use; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Quinolines - pharmacology; Quinolines - therapeutic use; Signal Transduction - drug effects; Signal Transduction - immunology; STAT3 inhibitor; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; T cell exhaustion; Transplantation Chimera - immunology; Treatment Outcome; Tumor-infiltrating lymphocytes; Xenograft Model Antitumor Assays; TAM; MDSC; Tumor-infiltrating lymphocytes; Humanized NOG-MHC dKO mouse; NOG; T cell exhaustion; ICB; MHC; TME; PBMC; TKI; TIL; Exhaustion marker; STAT3 inhibitor
• ISSN: 0165-2478; 1879-0542
• DOI: 10.1016/j.imlet.2019.10.003

•A combination therapy with anti-PD-1 antibody and STAT3 inhibitor was performed.•Humanized MHC-deficient NOG mouse was used for in vivo study against pancreatic cancer.•Unexpectedly, the combination remarkably reduced the anti-tumor effect and TIL numbers.•The combination of anti-PD-1 antibody with signal inhibitors should be carefully evaluated.•The present approach may be helpful to develop effective combination regimen using ICB. Recently, clinical studies using anti-immune checkpoint molecule antibodies have been successful in solid tumors, such as melanoma and non-small cell lung cancers. However, pancreatic cancers are still intractable and difficult to treat once recurrence or metastasis occurs; thus, novel combined use of immune checkpoint blockade (ICB) with molecular targeted drugs is considered a therapeutic option. Previously, we developed a novel humanized MHC-double knockout (dKO) NOG mouse model and demonstrated that an anti-PD-1 antibody or a STAT3 inhibitor showed anti-tumor effects through an immunological mechanism. In the current study, using a humanized mouse model, we aimed to develop a combination therapy with an anti-PD-1 antibody and a STAT3 inhibitor (STX-0119) for use in vivo against pancreatic cancer. In an in vitro investigation, STX-0119 showed weak to moderate cytotoxic activity against several pancreatic cancer cell lines, which exhibited activated pSTAT3 and weak PD-L1 expression. However, unexpectedly, an in vivo study indicated that the combination of the anti-PD-1 antibody with STX-0119 remarkably reduced the anti-tumor effect and TIL numbers despite the effective anti-tumor activity against pancreatic cancer was produced individually by STX-0119 and the anti-PD-1 antibody. These results suggested that the combination of an anti-PD-1 antibody with specific signal inhibiting drugs should be carefully evaluated to avoid unexpected side effects, and such studies might contribute to the development of an effective combination regimen of ICB with cancer-targeting drugs such as tyrosine kinase inhibitors (TKIs).