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

Satoko Koga; Hideya Onishi; Shogo Masuda; Akiko Fujimura; Shu Ichimiya; Kazunori Nakayama; Akira Imaizumi; Kenichi Nishiyama; Masayuki Kojima; Kei Miyoshi; Katsuya Nakamura; Masayo Umebayashi; Takashi Morisaki; Masafumi Nakamura

doi:10.1016/j.tranon.2021.101152

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

Transl Oncol. 2021 Sep;14(9):101152. doi: 10.1016/j.tranon.2021.101152. Epub 2021 Jun 13.

Authors

Affiliations

¹ 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.
² Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: ohnishi.hideya.928@m.kyushu-u.ac.jp.
³ Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
⁴ Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan.
⁵ Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
⁶ Department of Respiratory Surgery, Japan Community Health Care Organization Kyushu Hospital, Kitakyushu, Japan.
⁷ Fukuoka General Cancer Clinic, Fukuoka, Japan.

Abstract

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.

Keywords: Cancer immunotherapy strategy; Cancer suppression; Lung net; Lymphocyte activation; PTPN3.