TY - JOUR
T1 - Patched 1-interacting peptide represses fibrosis in pancreatic cancer to augment the effectiveness of immunotherapy
AU - Oyama, Yasuhiro
AU - Onishi, Hideya
AU - Koga, Satoko
AU - Murahashi, Mutsunori
AU - Ichimiya, Shu
AU - Nakayama, Kazunori
AU - Fujimura, Akiko
AU - Kawamoto, Makoto
AU - Imaizumi, Akira
AU - Umebayashi, Masayo
AU - Ohuchida, Kenoki
AU - Morisaki, Takashi
AU - Nakamura, Masafumi
N1 - Funding Information:
Supported by Japan Society for the Promotion of Science KAKENHI Grant Numbers JP 16K15593 and 18K08682.
Publisher Copyright:
© 2020 Lippincott Williams and Wilkins. All rights reserved.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Pancreatic ductal adenocarcinoma (PDAC) is resistant to immunotherapy. As a factor of resistance, the dense fibrosis of this cancer acts as a barrier to inhibit immune cell infiltration into a tumor. We examined the influence of a Hedgehog signal inhibitor, Patched 1-interacting peptide, on fibrosis, infiltration of immune cells, and immunotherapeutic effects on PDAC. We found that this peptide inhibited proliferation and migration of cancer-associated fibroblasts and cancer cells. Furthermore, this peptide reduced the production of extracellular matrix and transforming growth factor β1 in cancer-associated fibroblasts and induced expression of HLA-ABC in PDAC cells and interferon-γ in lymphocytes. In vivo, the peptide suppressed fibrosis of PDAC and increased immune cell infiltration into tumors. The combination of this peptide and an anti-programmed death-1 antibody augmented the antitumor effect, and this combination showed the same effect in experiments using cancer cells and autologous lymphocytes. These results indicate that, in addition to the direct effect of tumor suppression, the Patched 1-interacting peptide increases the infiltration of immune cells by reducing fibrosis of PDAC and consequently enhances the effect of immunotherapy. Therefore, treatment with this peptide may be a novel therapy with 2 different mechanisms: direct tumor suppression and enhancing the immune response against PDAC.
AB - Pancreatic ductal adenocarcinoma (PDAC) is resistant to immunotherapy. As a factor of resistance, the dense fibrosis of this cancer acts as a barrier to inhibit immune cell infiltration into a tumor. We examined the influence of a Hedgehog signal inhibitor, Patched 1-interacting peptide, on fibrosis, infiltration of immune cells, and immunotherapeutic effects on PDAC. We found that this peptide inhibited proliferation and migration of cancer-associated fibroblasts and cancer cells. Furthermore, this peptide reduced the production of extracellular matrix and transforming growth factor β1 in cancer-associated fibroblasts and induced expression of HLA-ABC in PDAC cells and interferon-γ in lymphocytes. In vivo, the peptide suppressed fibrosis of PDAC and increased immune cell infiltration into tumors. The combination of this peptide and an anti-programmed death-1 antibody augmented the antitumor effect, and this combination showed the same effect in experiments using cancer cells and autologous lymphocytes. These results indicate that, in addition to the direct effect of tumor suppression, the Patched 1-interacting peptide increases the infiltration of immune cells by reducing fibrosis of PDAC and consequently enhances the effect of immunotherapy. Therefore, treatment with this peptide may be a novel therapy with 2 different mechanisms: direct tumor suppression and enhancing the immune response against PDAC.
UR - http://www.scopus.com/inward/record.url?scp=85076345292&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076345292&partnerID=8YFLogxK
U2 - 10.1097/CJI.0000000000000305
DO - 10.1097/CJI.0000000000000305
M3 - Article
C2 - 31834207
AN - SCOPUS:85076345292
SN - 1524-9557
VL - 43
SP - 121
EP - 133
JO - Journal of Biological Response Modifiers
JF - Journal of Biological Response Modifiers
IS - 4
ER -
