Patched 1-interacting Peptide Represses Fibrosis in Pancreatic Cancer to Augment the Effectiveness of Immunotherapy

Abstract

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.

Development and Verification of the Hypoxia- and Immune-Associated Prognostic Signature for Pancreatic Ductal Adenocarcinoma

“…Accumulating lines of evidence reveal that hypoxia interacts directly or indirectly with the immune status in the PDAC microenvironment (16,17), yet the mechanism has been under-investigated. Based on the fact that T-cell infiltration (18), DC function (19), etc. are impaired under hypoxia, Yamasaki et al suggest in their review that immunotherapy can only be successful if these hypoxia-immune interaction issues are addressed properly (2).…”

GLI2 but not GLI1/GLI3 plays a central role in the induction of malignant phenotype of gallbladder cancer

“…In addition, the TME has also attracted increased attention (58). We previously reported that inhibition of the Hh signaling pathway suppressed pancreatic cancer fibrosis and promoted intratumoral lymphocyte infiltration in pancreatic cancer (55). As our results indicated that GLI2 may promote tumor fibrosis, we analyzed the association between GLI2 expression and TILs in GBC specimens and found an inverse correlation between GLI2 expression in tumor cells and TIL counts.…”

“…This result indicated that GLI2 may be involved in tissue fibrosis in GBC. In our past study of pancreatic cancer, we used pancreatic cancer cells and pancreatic tissue-derived cancer-associated fibroblasts (CAFs) to generate tumors in a xenograft model (55), whereas the reproduction of human pancreatic cancer tissue was not perfect because inducing fibrosis resembling the actual cancer tissue was incomplete. In addition, CAFs derived from GBC tissues has not been established.…”

PTPN3 is a potential target for a new cancer immunotherapy that has a dual effect of T cell activation and direct cancer inhibition in lung neuroendocrine tumor

“…PTPs regulate tyrosine phosphorylation in concert with PTK [27] . Low expression of PTPN3, like PTK, may lead to reduction of fibrosis because of the interaction between PTK and PTP, which makes it easier for tumor-infiltrating lymphocytes to infiltrate and increase in tissues [28] . Various factors have been reported to be involved in fibrosis.…”