Koga Satoko, Onishi Hideya, Masuda Shogo, Fujimura Akiko, Ichimiya Shu, Nakayama Kazunori, Imaizumi Akira, Nishiyama Kenichi, Kojima Masayuki, Miyoshi Kei, Nakamura Katsuya, Umebayashi Masayo, Morisaki Takashi, Nakamura Masafumi
Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Transl Oncol. 2021 Sep;14(9):101152. doi: 10.1016/j.tranon.2021.101152. Epub 2021 Jun 13.
In our previous study, we found that inhibition of protein tyrosine phosphatase non-receptor type 3 (PTPN3), which is expressed in lymphocytes, enhances lymphocyte activation, suggesting PTPN3 may act as an immune checkpoint molecule. However, PTPN3 is also expressed in various cancers, and the biological significance of PTPN3 in cancer cells is still not well understood, especially for lung neuroendocrine tumor (NET).Therefore, we analyzed the biological significance of PTPN3 in small cell lung cancer and examined the potential for PTPN3 inhibitory treatment as a cancer treatment approach in lung NET including small cell lung cancer (SCLC) and large cell neuroendocrine cancer (LCNEC). Experiments in a mouse xenograft model using allo lymphocytes showed that PTPN3 inhibition in SCLC cells enhanced the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In addition, PTPN3 was associated with increased vascularization, decreased CD8/FOXP3 ratio and cellular immunosuppression in SCLC clinical specimens. Experiments in a mouse xenograft model using autocrine lymphocytes also showed that PTPN3 inhibition in LCNEC cells augmented the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In vitro experiments showed that PTPN3 is involved in the induction of malignant traits such as proliferation, invasion and migration. Signaling from PTPN3 is mediated by MAPK and PI3K signals via tyrosine kinase phosphorylation through CACNA1G calcium channel. Our results show that PTPN3 suppression is associated with lymphocyte activation and cancer suppression in lung NET. These results suggest that PTPN3 suppression could be a new method of cancer treatment and a major step in the development of new cancer immunotherapies.
在我们之前的研究中，我们发现抑制淋巴细胞中表达的非受体型3蛋白酪氨酸磷酸酶（PTPN3）可增强淋巴细胞活化，提示PTPN3可能作为一种免疫检查点分子发挥作用。然而，PTPN3也在多种癌症中表达，其在癌细胞中的生物学意义仍未得到充分理解，尤其是对于肺神经内分泌肿瘤（NET）。因此，我们分析了PTPN3在小细胞肺癌中的生物学意义，并研究了抑制PTPN3作为包括小细胞肺癌（SCLC）和大细胞神经内分泌癌（LCNEC）在内的肺NET癌症治疗方法的潜力。使用同种异体淋巴细胞的小鼠异种移植模型实验表明，抑制SCLC细胞中的PTPN3可增强PTPN3抑制的活化淋巴细胞的抗肿瘤作用。此外，在SCLC临床标本中，PTPN3与血管生成增加、CD8/FOXP3比值降低和细胞免疫抑制有关。使用自分泌淋巴细胞的小鼠异种移植模型实验还表明，抑制LCNEC细胞中的PTPN3可增强PTPN3抑制的活化淋巴细胞的抗肿瘤作用。体外实验表明，PTPN3参与增殖、侵袭和迁移等恶性特征的诱导。PTPN3的信号传导是通过CACNA1G钙通道经酪氨酸激酶磷酸化由MAPK和PI3K信号介导的。我们的结果表明，在肺NET中，抑制PTPN3与淋巴细胞活化和癌症抑制相关。这些结果提示，抑制PTPN3可能是一种新的癌症治疗方法，也是新型癌症免疫疗法发展中的重要一步。
