In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4911-4911
Abstract:
[Background] In many solid cancers, constitutive activation of JAK/ signal transducers and activators of transcription (STAT) signaling pathway is associated with poor prognosis. Constitutive JAK/STAT signaling enhances the expression of cyclins and anti-apoptosis proteins, leads to the increased tumor cell proliferation and survival. Furthermore, one of the immune checkpoint molecules programmed cell death 1 ligand 1 (PD-L1), which is involved in the suppression of T cell mediated antitumor immunity, is induced by STATs. Suppressor of cytokine signaling (SOCS)-1 is a negative feedback molecule, which is induced by JAK/STAT signaling and inhibits the JAK activity, resulted in the suppression of JAK/STAT signaling. This study aimed to reveal the antitumor effects by SOCS-1 in vitro and in vivo. [METHODS] Five human OC cell lines (OVCAR-3, SKOV-3, RMG-1, A2780, ES-2) and 4 murine cancer cell lines (B16F10, LLC, 4T1, CT26) were assessed. SOCS-1 or LacZ were overexpressed by adenoviral vector. Anti-proliferative effect was assessed by WST-8 assay. Female BALB/c mice were injected with CT26 for subcutaneous xenograft experiments. AdSOCS-1 or AdLacZ was intra-tumorally administered every other day and PD-L1 expression in tumor cells and activation levels of tumor infiltrated T cells were analyzed by flow cytometry. [RESULT] Overexpression of SOCS-1 inhibited proliferation of all cancer cell lines. Three OC (OVCAR-3, SKOV-3, ES2) and all murine cancer constitutively expressed PD-L1. Expression levels of PD-L1 in OVCAR-3 and CT26 cells were downregulated about 30% compared with control by overexpressed SOCS-1 in vitro. In CT26 allografted model, SOCS-1 treatment significantly inhibited tumor growth (62.2±5.2%, P & lt;0.01)and suppressed expression of PD-L1 on CT26 cells in the tumor (65.2±8.4%, P & lt;0.05). Granzyme B and CD107a expression of intratumorally infiltrated CD8 T cells were increased more than 50% (P & lt;0.05) in the AdSOCS-1 injected group compared with AdLacZ injected group. PD-L1 Fc fusion protein significantly inhibited antitumor effect of SOCS-1. [Conclusion] SOCS-1 mediated inhibition of JAK/STAT signaling shows not only direct antitumor effect against tumor cells but also enhances T cell mediated anti-tumor immunity in vivo by downregulating the expression of PD-L1 on tumor cells and preventing the interaction of PD-1/ PD-L1. Citation Format: Satoshi Nakagawa, Satoshi Serada, Satoko Matsuzaki, Yutaka Ueda, Kiyoshi Yoshino, Minoru Fujimoto, Tadashi Kimura, Tetsuji Naka. SOCS-1 inhibits tumor growth by enhancing T cell mediated antitumor immunity related to PD-L1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4911.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2016-4911
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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