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Updated: Jul 3, 2026
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Melanoma cell-derived LAG-3 enhances CXCL1/8-driven MDSCs recruitment and immune escape via TRIM28-mediated IκBα
Nina Xue1, Hang Gong2, Wenxia Chen2
1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Key Technologies for Preclinical Research and Development of Innovative Drugs in Pharmacokinetics and Pharmacodynamics, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Introduction:
Lymphocyte activation gene 3 (LAG-3) is recognized as an important inhibitory receptor on T cells, and LAG-3-targeted therapy has been approved for advanced melanoma treatment. Recently, LAG-3 has been reported to be expressed on tumor cells. However, the potential effects and underlying mechanisms of tumor cell-derived LAG-3 in mediating tumor growth and immunosuppression remain unclear.
Objectives:
This study aimed to evaluate the role of tumor cell-derived LAG-3 within the tumor microenvironment (TME) and the efficacy of anti-LAG-3 combination therapy against melanoma.
Methods:
The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, single-nuclear RNA sequencing database and tissue microarray analyses were conducted to detect the LAG-3 gene and protein expressions. The biological functions and underlying mechanism of tumor cell-derived LAG-3 in tumor growth and immunosuppression were investigated using phospho-array, RNA-seq, co-immunoprecipitation, flow cytometry, co-culture systems, and various tumor-bearing mouse models.
Results:
Our findings revealed that LAG-3 was present in a subpopulation of cancer cells and clinical melanoma specimens associated with poorer prognosis. High LAG-3 expression on tumor cells not only contributed to the proliferation and metastasis of melanoma cells, but also promoted the recruitment of myeloid-derived suppressor cells (MDSCs) and dysfunctional CD8+ T cells into the TME. Notably, depletion of MDSCs counteracted the pro-tumor activity of tumor cell-derived LAG-3. Mechanistically, LAG-3 overexpression triggered CXCL1 and CXCL8 production of melanoma cells by enhancing TRIM28-mediated IκBα ubiquitination and degradation, which in turn activated the NF-κB pathway and fostered tumor growth and an immunosuppressive microenvironment. Intriguingly, mice bearing LAG-3-overexpressing melanoma cells showed reduced survival but responded to anti-LAG-3 antibody therapy. Furthermore, inhibiting the CXCL1/8-CXCR2 axis sensitized LAG-3-overexpressing melanoma to anti-LAG-3 antibody.
Conclusion:
This study firstly identified LAG-3 as a pro-tumor factor and a predictor for anti-LAG-3 immunotherapy efficacy. Combined CXCL1/8-CXCR2 inhibitor and anti-LAG-3 treatment may represent a promising therapeutic strategy for LAG-3-driven tumor.
