No 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.

Background/Aim: Small-cell lung cancer (SCLC) remains one of deadliest types of cancers. Cisdiamminedichloroplatinum (CDDP) is a key chemotherapeutic agent for SCLC, however, its therapeutic effect is limited. Recently, hypoxia in the cancer microenvironment has been suggested to influence the effect of cancer therapy. Materials and Methods: Using small interfering RNA inhibition of leukocyte common antigen-related interacting protein alpha 4 (liprin-α4), and of hypoxia-inducible factor (HIF)-1α, proliferation, invasion, migration and chemosensitivity were investigated in SBC-5 SCLC cells, under normoxia and hypoxia. Results: Liprin-α4 was found to contribute to proliferation, but not migration and invasion of SBC-5 cells both under normoxia and hypoxia. Inhibition of liprin-α4 increased chemosensitivity of SBC-5 cells under hypoxia. Liprin-α4 signaling occurs through mitogen-activated protein kinase pathways via activation of HIF1α expression. Inhibition of HIF1α reduced proliferation and increased chemosensitivity of SBC-5 cells under hypoxia. Conclusion: Liprin-α4 inhibition may enhance the effect of CDDP and liprin-α4 might be a novel therapeutic target in SCLC.Small-cell lung cancer (SCLC) is still a refractory cancer for which there are few therapeutic strategies. Cisdiamminedichloroplatinum (CDDP) is a key chemotherapeutic agent, however, its effect is limited. Developing a new effective therapeutic strategy against SCLC and increasing the effect of existing agents is earnestly required.The microenvironment surrounding cancer tissue is important in considering cancer therapy. This microenvironment includes tumor-infiltrating immune cells, fibrosis, and desmoplasia, as well as cytokines and other molecules. Hypoxia is also thought to occur in the cancer microenvironment. The tumor local site is extremely hypoxic, with an oxygen concentration of approximately 1% O 2 (1). Biological functioning is altered under hypoxia. Therefore, the cell phenotype should especially be considered when investigating proliferation, invasion, and chemosensitivity under hypoxia rather than under normoxia which is a usual experimental condition.Liprins are major protein constituents of synapses and play a pivotal role in the organization of synaptic vesicles and neurotransmitter receptors (2). Liprin-α belongs to the LAR family of receptor protein tyrosine phosphatase (3, 4). Among liprin members, liprin-1α is well researched and recently its interaction with some cancer types has been reported (5, 6). On the other hand, the role of liprin-α4 remains unclear with regard to cancer biology. Previously we showed that liprin-α4 has potential as a new therapeutic target for refractory pancreatic cancer (7). In the present study, we evaluated whether liprin-α4 might be a therapeutic target in SCLC, which like pancreatic cancer is a refractory type of neuroendocrine cancer. Materials and MethodsCell culture and reagents. A human SCLC cell line (SBC-5: American Type Culture Collection, Manassas, VA, USA) was maintained in RPMI-1640 me...

Highlights PTPN3 suppression associates with lymphocyte activation and cancer suppression. PTPN3 is involved in the induction of malignant traits. PTPN3 is associated with cellular immunosuppression. Signals from PTPN3 go through MAPK and PI3K signaling. PTPN3-inhibited lung NET cells enhance PTPN3-suppressed activated lymphocytes.

These results suggest that RBPJ and MAML3 could be new therapeutic targets for SCLC, however, chemosensitivity may be reduced in combinational use with other chemo-therapeutic agents.