Fibrinogen like protein-1 knockdown suppresses the proliferation and metastasis of TU-686 cells and sensitizes laryngeal cancer to LAG-3 blockade

Abstract

Objective To detect the expression of fibrinogen like protein-1 (FGL-1) in laryngeal cancer and evaluate its effect on tumor proliferation, metastasis, and antitumor immunity. Methods ELISA and immunohistochemistry were performed to detect FGL-1 expression in laryngeal cancer. The effects of FGL-1 knockdown on the proliferation, cell cycle progression, apoptosis, migration, and invasion of laryngeal cancer cells were evaluated by the CCK-8, colony formation, flow cytometry, Transwell migration, and western blot assays. We detected changes in tumorigenesis and drug response in vivo following FGL-1 knockdown as well as the effects of anti-LAG3 immunotherapy. Immunohistochemistry was performed to determine CD8 and LAG-3 expression in mouse tumor tissues. Results FGL-1 was highly expressed in the plasma and tumor tissues of laryngeal cancer patients. FGL-1 knockdown suppressed the proliferation of TU-686 cells and inhibited the migration and invasion of laryngeal cancer by blocking epithelial-to-mesenchymal transition. Moreover, silencing FGL-1 inhibited tumorigenicity in vivo and synergized with anti-LAG3 immunotherapy. Conclusions We confirmed the high expression of FGL-1 in laryngeal cancer and identified FGL-1 as a potential marker for immunotherapy in laryngeal cancer.

Aspirin and immunotherapy: a Faustian bargain?

“…Combination therapy with a PD-L1 inhibitor and AGK2 resulted in further increases in antitumor immunity. An association between FGL1 inhibition and antitumor immune responses has been reported in other studies ( 1 , 3 ). Wang et al ( 3 ) implanted FGL1-knockout mice with colon cancer cells and found diminished tumor growth compared with controls.…”

“…One important consideration is whether tumor cell death and improved survival in this study were caused by DNA damage incurred by HDAC inhibition rather than via antitumor immunity — indeed, the authors did not assess DNA damage ( 4 ). However, the authors did demonstrate enhanced tumor invasion by immune cells in response to FGL1 acetylation ( 4 ), and past research has shown FGL1–LAG-3 interaction ( 1 , 3 ). Thus, it is likely that antitumor immunity at least plays a role in these findings.…”

“…Cancer evades detection by the immune system by utilizing various modulators, such as programmed cell death protein 1 (PD-1) and lymphocyte-activating gene 3 (LAG-3) ( 1 ). LAG-3 is expressed on the surface of T cells, and its activation suppresses T cell antigen–mediated activation, signaling, and proliferation ( 2 , 3 ).…”

“…LAG-3 is expressed on the surface of T cells, and its activation suppresses T cell antigen–mediated activation, signaling, and proliferation ( 2 , 3 ). Fibrinogen-like protein 1 (FGL1) has been identified as a ligand of LAG-3 and is implicated in several malignancies ( 1 , 2 ). Antibody-mediated knockdown of FGL1 expression has been shown to increase antigen-mediated T cell activation.…”

“…Furthermore, depletion of B and T cells mitigated the antitumor effects of FGL1 and LAG-3 inhibition, suggesting that FGL1 contributes to tumor growth by inhibiting antitumor immunity ( 3 ). Huang et al ( 1 ) found that FGL1 silencing was associated with increased intratumoral T cell activity in a murine model of squamous cell carcinoma. Thus, it is unsurprising that the combination of FGL1 and PD-1 inhibition, which would be expected to bolster the antitumor immune response, resulted in further benefits in tumor control and survival in the Lin et al study ( 4 ).…”