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

• Published in: Journal of cancer research and clinical oncology 2023-11, Vol.149 (16), p.14619-14630
• Main Authors: Iwamoto, Naoya, Onishi, Hideya, Masuda, Shogo, Imaizumi, Akira, Sakanashi, Keita, Morisaki, Shinji, Nagao, Shinjiro, Koga, Satoko, Ozono, Keigo, Umebayashi, Masayo, Morisaki, Takashi, Nakamura, Masafumi
• Format: Article
• Language: English
• Subjects: Antigen-presenting cells; Antigens; Cancer; Cancer immunotherapy; Cancer Research; CD80 antigen; Cell activation; Chemokine receptors; cytokines; Cytotoxicity; Dendritic cells; Enzyme-linked immunosorbent assay; Granzyme B; Hematology; Histocompatibility antigen HLA; HLA antigens; humans; Immune checkpoint; Immunotherapy; Internal Medicine; Intracellular; Intracellular signalling; Kinases; Leukocyte migration; Lung carcinoma; lungs; Lymphocytes; Lymphocytes T; MAP kinase; Medicine; Medicine & Public Health; mitogen-activated protein kinase; Monocytes; mononuclear leukocytes; necrosis; neoplasm cells; Oncology; Peripheral blood; Protein-tyrosine-phosphatase; RNA; Squamous cell carcinoma; α-Interferon
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-023-05250-8

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.