Inhibition of PTPN3 Expressed in Activated Lymphocytes Enhances the Antitumor Effects of Anti-PD-1 Therapy in Head and Neck Cancer, Especially in Hypoxic Environments.

In the tumor microenvironment, wherein cytotoxic lymphocytes interact with cancer cells, lymphocyte exhaustion, an immune checkpoint inhibitor target, is promoted. However, the efficacy of these inhibitors is limited, and improving response rates remains challenging. We previously reported that protein tyrosine phosphatase nonreceptor type (PTPN) 3 is a potential immune checkpoint molecule for activated lymphocytes and that PTPN3 inhibition should be a focus area for cancer immunotherapy development. Therefore, in this study, we focused on PTPN3-suppressive therapy in terms of lymphocyte exhaustion under hypoxic conditions, which are a cancer microenvironment, and investigated measures for improving the response to anti-programmed death receptor (PD)-1 antibody drugs. We found that PTPN3 expression was upregulated in activated lymphocytes under hypoxic conditions, similar to the findings for other immune checkpoint molecules, such as PD-1, T cell immunoglobulin mucin-3, and lymphocyte-activation gene-3; furthermore, it functioned as a lymphocyte exhaustion marker. In addition, PTPN3-suppressed activated lymphocytes promoted the mammalian target of rapamycin (mTOR)-Akt signaling pathway activation and enhanced proliferation, migration, and cytotoxic activities under hypoxic conditions. Furthermore, PTPN3 suppression in activated lymphocytes increased PD-1 expression and enhanced the antitumor effects of anti-PD-1 antibody drugs against head and neck cancer in vitro and in vivo. These results suggest that the suppression of PTPN3 expression in activated lymphocytes enhances the therapeutic effect of anti-PD-1 antibody drugs in head and neck cancer, especially under hypoxic conditions that cause lymphocyte exhaustion.

PTPN3 inhibition contributes to the activation of the dendritic cell function to be a promising new immunotherapy target.

PURPOSE: In a previous study, protein tyrosine phosphatase non-receptor type (PTPN) 3 was identified as an immune checkpoint molecule in lymphocytes, and its potential as a novel target for cancer immunotherapy was anticipated. However, evaluation of dendritic cell (DC) function as antigen-presenting cells is critical for the development of immunotherapy. In this study, we aimed to analyze the biological effect of PTPN3 on DCs induced from human peripheral blood monocytes obtained from healthy individuals. METHODS: We used short-interfering RNA to knock down PTP3 in DCs. For DC maturation, we added cancer cell lysate and tumor necrosis factor-α/interferon-α to immature DCs. In the cytotoxic assay, the target cancer cells were SBC5, unmatched with DCs from healthy human leukocyte antigen (HLA)-A24, or Sq-1, matched with DCs. Enzyme-linked immunosorbent assay was used to determine the amount of cytokines. To examine the intracellular signaling system, intracellular staining was used. RESULTS: PTPN3 knockdown significantly increased the number of DCs, expression of CD80 and chemokine receptor (CCR)7, and production of interleukin-12p40/p70 in mature DCs. In the HLA-A24-restricted DC and human lung squamous cell carcinoma cell cytotoxic assay, inhibition of PTPN3 expression in mature DCs induced cytotoxic T lymphocytes with increased production of INF-γ and granzyme B, and enhanced toxicity against cancer cells and migration to cancer. Furthermore, inhibition of PTPN3 expression activated the mitogen-activated protein kinase pathway in DCs. CONCLUSION: Based on our findings, inhibition of PTPN3 expression could contribute to the development of novel cancer immunotherapies that activate not only lymphocytes but also DCs.

C4orf47 Contributes to the Induction of Stem-like Properties in Gallbladder Cancer Under Hypoxia.

BACKGROUND/AIM: Gallbladder cancer (GBC) is a refractory cancer with poor prognosis. Recently, therapy targeting the tumor microenvironment (TME) has gained attention. Cancer hypoxia is a significant factor in the tumor microenvironment (TME). Our research has shown that hypoxia activates several molecules and signaling pathways that contribute to the development of various types of cancer. Our analysis indicated that C4orf47 expression was up-regulated in a hypoxic environment and had a role in the dormancy of pancreatic cancer. There are no other reports on the biological significance of C4orf47 in cancer and its mechanism is still unknown. This study analyzed how C4orf47 affects refractory GBC to develop a new effective therapy for GBC. MATERIALS AND METHODS: Two human gallbladder carcinomas were used to examine how C4orf47 affects proliferation, migration, and invasion. C4orf47 was silenced using C4orf47 siRNA. RESULTS: C4orf47 was over-expressed in gallbladder carcinomas under hypoxic conditions. C4orf47 inhibition increased the anchor-dependent proliferation and decreased the anchor-independent colony formation of GBC cells. C4orf47 inhibition reduced epithelial-mesenchymal transition and suppressed migration and invasiveness of GBC cells. C4orf47 inhibition decreased CD44, Fbxw-7, and p27 expression and increased C-myc expression. CONCLUSION: C4orf47 enhanced invasiveness and CD44 expression, and reduced anchor-independent colony formation, suggesting that C4orf47 is involved in plasticity and the acquisition of the stem-like phenotype of GBC. This information is useful for the development of new therapeutic strategies for GBC.

PTPN3 Could Βe a Therapeutic Target of Pancreatic Cancer.

BACKGROUND/AIM: Recently, protein tyrosine phosphatase non-receptor type 3 (PTPN3) has gained attention. However, the role of PTPN3 in cancer has not been fully elucidated. In the present study, we analyzed the role of PTPN3 in pancreatic cancer and investigated whether PTPN3 could be a new therapeutic target for pancreatic cancer. MATERIALS AND METHODS: Two pancreatic ductal adenocarcinoma (PDAC) cell lines were used as target cells. Cell proliferation was investigated using cell counting and a xenograft mouse model. Migration and invasion were analyzed using Transwell inserts. Activation-related signaling molecules were examined by western blotting. RESULTS: PTPN3 contributes to the proliferation, migration, and invasion of PDAC cells in vitro. PTPN3 promotes tumor growth in a mouse xenograft model, an action mediated partially through the MAPK pathway. CONCLUSION: PTPN3 could be a new therapeutic target for pancreatic cancer.