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PTPN3 Expressed in Activated T Lymphocytes Is a Candidate for a Non-Antibody-Type Immune Checkpoint Inhibitor

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PTPN3 Expressed in Activated T Lymphocytes Is a Candidate for a Non-Antibody-Type Immune Checkpoint Inhibitor Cancer Immunology, Immunotherapy (2019) 68:1649–1660 https://doi.org/10.1007/s00262-019-02403-y ORIGINAL ARTICLE PTPN3 expressed in activated T lymphocytes is a candidate for a non‑antibody‑type immune checkpoint inhibitor Akiko Fujimura1 · Kazunori Nakayama1 · Akira Imaizumi1 · Makoto Kawamoto1 · Yasuhiro Oyama1 · Shu Ichimiya1 · Masayo Umebayashi2 · Norihiro Koya2 · Takashi Morisaki2 · Takashi Nakagawa3 · Hideya Onishi1 Received: 20 February 2019 / Accepted: 23 September 2019 / Published online: 27 September 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract It has been shown that protein tyrosine phosphatase non-receptor type (PTPN) 3 inhibits T-cell activation. However, there is no defnitive conclusion about how the inhibition of PTPN3 in lymphocytes afects immune functions in human lym- phocytes. In the present study, we showed that PTPN3 inhibition signifcantly contributes to the enhanced activation of activated human lymphocytes. The PTPN3 expression of lymphocytes was signifcantly increased through the activation process using IL-2 and anti-CD3 mAb. Interestingly, inhibiting the PTPN3 expression in activated lymphocytes signifcantly augmented the proliferation, migration, and cytotoxicity through the phosphorylation of zeta-chain-associated protein kinase 70 (ZAP-70), lymphocyte-specifc protein tyrosine kinase (LCK), and extracellular signal-regulated kinases (ERK). Lym- phocyte activation by PTPN3 inhibition was observed only in activated CD3+ T cells and not in NK cells or resting T cells. In therapy experiments using autologous tumors and lymphocytes, PTPN3 inhibition signifcantly augmented the number of tumor-infltrated lymphocytes and the cytotoxicity of activated lymphocytes. Our results strongly imply that PTPN3 acts as an immune checkpoint in activated lymphocytes and that PTPN3 inhibitor may be a new non-antibody-type immune checkpoint inhibitor for cancer therapy. Keywords PTPN3 · Activated lymphocyte · Immune checkpoint · Cancer immunology · Immunotherapy Abbreviations PTPN Protein tyrosine phosphatase non-receptor type DALs DC-stimulated activated lymphocytes shRNA Short hairpin RNA ERK Extracellular signal-regulated kinases Zap-70 Zeta-chain-associated protein kinase 70 GAPDH Glyceraldehyde-3-phosphate dehydrogenase LCK Lymphocyte-specifc protein tyrosine kinase MOI Multiplicity of infection Introduction ntTILs Non-tumor-tissue-infltrating-administrated lymphocytes Recently, remarkable progress has been made in immuno- PTP Protein tyrosine phosphatase therapy. Many authors have reported the efectiveness of immune check point inhibitors [1, 2]. However, the response rate is still limited, and many severe adverse efects are Electronic supplementary material The online version of this reported, while the treatment remains costly. Therefore, new article (https ://doi.org/10.1007/s0026 2-019-02403 -y) contains methodologies, including combination therapy with existing supplementary material, which is available to authorized users. antibody agents, are still urgently needed. * Hideya Onishi Many molecules that act as immune checkpoint inhibitors [email protected] have been discovered and investigated, including programmed cell death (PD)-1, programmed cell death ligand-1 (PD-L1), 1 Department of Cancer Therapy and Research, Graduate PD-L2, cytotoxic T-lymphocyte associated antigen (CTLA)-4, School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan T-cell immunoglobulin and mucin domain (TIM)-3, and lym- phocyte activation gene (LAG)-3 [1–4]. However, all of these 2 Fukuoka General Cancer Clinic, Fukuoka, Japan molecules are antibody-type immune checkpoint inhibitors 3 Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Vol.:(0123456789)1 3 1650 Cancer Immunology, Immunotherapy (2019) 68:1649–1660 and no non-antibody-type immune checkpoint inhibitors are supplemented with 2000 units/ml penicillin, 10 mg/ml available at the present time. streptomycin, 0.5% human serum, and 200 U/ml IL-2. After The actions of protein tyrosine phosphatase non-receptor 30–60 min, the supernatant was discarded, and adherent type (PTPN) 3, which removes phosphorylation from protein cells were cultured for 4–7 days in new medium supple- tyrosyl residues, may be the opposite of those of protein mented with 50 ng/ml IL-4 (Primmune) and 100 ng/ml GM- tyrosine kinase [5]. The role of PTPN3 in lymphocytes is CSF (Primmune). Following this, 200 µg of SUIT-2 tumor still controversial. PTPN3 has been shown to inhibit T-cell lysate was added to the culture. After 4–12 h, TNF-α (500 U/ activation [5]. On the other hand, some authors have dem- ml; Gentaur Molecular Products, Brussels, Belgium) and onstrated that PTPN3 is dispensable for the negative regu- 500 U/ml IFN-α (MSD, Kenilworth, NJ, USA) were added lation of T-cell activation using PTPN3 knockout mice [6]. to the culture. After 1 day of incubation, lymphocytes were However, how the inhibition of PTPN3 afects the immune added to the culture and cultured for 4 days. Non-adherent function against cancer in human activated lymphocytes fractions were collected and cultured in RPMI medium sup- remains unclear. The development of new immunotherapy is plemented with 200 U/ml IL-2 in 2.5 µg/ml OKT3-coated signifcantly important for solving problems of the response culture plates for 5 days. Cells were then collected as DALs. rate, treatment cost, and adverse efects of existing antibody agents. In the present study, we focused on PTPN3 in acti- Cancer cell culture vated lymphocytes as a target for non-antibody-type immune checkpoint inhibitors and investigated the functions of lym- The human pancreatic ductal adenocarcinoma cell line phocytes by inhibiting PTPN3. SUIT-2 and human tongue squamous cell carcinoma cell line SCC-9 were maintained in RPMI 1640 medium sup- Materials and methods plemented with 10% fetal calf serum (FCS; Thermo Fisher Scientifc, Waltham, MA, USA) and antibiotics (2000 units/ Induction of activated lymphocytes ml of penicillin and 10 µg/ml of streptomycin). In vitro and in vivo experiments used peripheral blood RNA interference mononuclear cells (PBMCs) collected from the heparinized peripheral blood of ten healthy volunteers and three cancer Nucleotide sequences for short hairpin RNA (shRNA) tar- patients via HISTOPAQUE-1077 (Merck KGaA, Darm- geting PTPN3 were as follows: shPTPN3#1, CAATCA GAA stadt, Germany) density gradient centrifugation. PBMCs GCA GAA TCC TGC TAT A; and shPTPN3#2, GAC AGC were cultured in RPMI-1640 (Nacalai Tesque, Kyoto, Japan) TAC TTA GTC TTG ATC CGT A. These oligonucleotides supplemented with 0.5% human serum, 2000 units/ml peni- were ligated in the plasmid vector (pcDNA™6.2-GW/Em- cillin (Meijiseika, Tokyo, Japan), 10 µg/ml streptomycin miR,#K4934-00; Thermo Fisher Scientifc). This plasmid (Meijiseika), and 200 U/ml IL-2 (Primmune, San Diego, vector was then co-transfected with the ViraPower™ Pack- CA, USA) in a 2.5 µg/ml anti-CD3 monoclonal antibody aging Mix (included in BLOCK-iT™ Lentiviral Poll l miR (OKT3, JANSSEN PHARMACEUTICAL K.K., Osaka, RNAi Expression Systems; Thermo Fisher Scientifc) into Japan)-coated T-75/T-25 fask or 6-well plate for 7 days. the 293FT cell line to produce the lentiviral stock. PTPN3 Non-adherent fractions were collected as activated lympho- transfection using lentivirus in lymphocytes was performed cytes. In the microarray analysis, activated lymphocytes from culture days 3–6. from two patients with pancreatic cancer and lung cancer were used. In in vivo therapy experiments, tumor cells and DNA microarray autologous-activated lymphocytes from a patient with ovar- ian cancer were used. The methodology of the DNA microarray which we used For CD3+CD4+NKG2D− T cell and CD3+CD8+NKG2D+ has been described previously [8]. Intensity-based Z-scores T-cell selection, a magnetic cell separation system was used and ratios (nonlog-scale fold-change) were calculated from (Mojosort Human CD4 T-cell isolation kit and Mojosort the normalized signal intensities of each probe to compare Human CD8 T-cell isolation kit, respectively; Biolegend, lymphocytes before and after activation. The registration San Diego, CA, USA). numbers are GSE86293 and GSE89328. Induction of dendritic cell (DC)‑stimulated activated Reverse transcription (RT)‑polymerase chain lymphocytes (DALs) reaction (PCR) DC-stimulated activated lymphocytes were induced as Total RNA was extracted using a High Pure RNA Isola- described previously [7]. PBMCs were incubated in RPMI tion kit (Roche, Basel, Switzerland) and quantified by 1 3 Cancer Immunology, Immunotherapy (2019) 68:1649–1660 1651 spectrophotometry (Ultrospec 2100 Pro; Amersham Phar- USA), anti-ERK1/2 (1:1000, No. 9102; Cell Signaling Tech- macia Biotech, Piscataway, NJ, USA). For RT-PCR, 1.0 μg nology, Danvers, MA, USA), anti-pERK (1:1000, No. 9101; of RNA was reverse transcribed to cDNA with the Verso Cell Signaling Technology), anti-Zap (1:2000, No. 3165; cDNA Synthesis Kit (Thermo Fisher Scientifc) according Cell Signaling Technology), anti-pZap (1:1000, No. 2701; to the manufacturer’s protocol. RT-PCR reactions were per- Cell Signaling Technology), anti-Lck (1:1000, No. 2657; formed using MasterMix kit (Qiagen, Valencia, CA, USA). Cell Signaling Technology), anti-pSrc (1:1000, No. 2101; All primer sets used were as follows: PTPN3 forward, Cell Signaling Technology), and anti-α tubulin (1:1000; 5′-TGG TAT CGTG GAA GGA CTCA-3′; reverse, 5′-AGC Sigma Aldrich) overnight
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