Tumor-derived immunoglobulin-like transcript 3 inhibition reshapes the immunosuppressive tumor microenvironment and potentiates programmed cell death ligand 1 blockade immunotherapy in lung adenocarcinoma
The low response rate of current immune checkpoint inhibitors in cancer has necessitated the development of new immune targets.Survival and public databases analyses were performed to determine the clinical significance of immunoglobulin-like transcript 3 (ILT3). The impact of ILT3 and apolipoprotei...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-06-01
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| Series: | Translational Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523325001123 |
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| Summary: | The low response rate of current immune checkpoint inhibitors in cancer has necessitated the development of new immune targets.Survival and public databases analyses were performed to determine the clinical significance of immunoglobulin-like transcript 3 (ILT3). The impact of ILT3 and apolipoprotein E (APOE) on tumor-associated macrophage (TAM) recruitment and polarization were evaluated by transwell assay, flow cytometry (FCM), and real-time PCR, while their impact on T cell survival and cytotoxicity was detected by CFSE, apoptotic assay, FCM and ELISA. These pro-tumoural activity of (an ortholog of ILT3 in mouse) were verified in vivo models.Survival and public databases analyses revealed that high ILT3 expression was significantly associated with worse prognosis in lung adenocarcinoma (LUAD), but not in squamous cell carcinoma. The same association was observed with its ligand, APOE. In vitro assays demonstrated that tumor-derived ILT3/APOE promoted recruitment and M2-like polarization of TAMs in LUAD and directly inhibited T cell proliferation and cytotoxicity. In vivo knockdown of gp49b enhanced anti-tumor immunity and suppressed tumor progression by counteracting TAM- and dysfunctional T cell-induced tumor microenvironment immunosuppression. Furthermore, combined inhibition of gp49b and programmed cell death ligand 1 (PD-L1) showed the most drastic tumor regression in C57BL/6 mice models.Tumor-derived ILT3 overexpression suppresses anti-tumor immunity by recruiting M2-like TAMs and impairing T cell activities, while ILT3 inhibition counteracts this immunosuppression and enhances the efficacy of PD-L1 blockade in LUAD. Thus, ILT3 could be a promising novel immunotherapeutic target for combined immunotherapy. |
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| ISSN: | 1936-5233 |