Galectin-9 and Tim-3 in gastric cancer: a checkpoint axis driving T cell exhaustion and Treg-mediated immunosuppression independently of anti-PD-1 blockade
Immune checkpoint inhibitors have significantly advanced the treatment of gastric cancer (GC), yet therapeutic resistance remains common due to the immunosuppressive tumor microenvironment and redundancy among inhibitory checkpoints. Tim-3 (HAVCR2) is an emerging immune checkpoint receptor implicate...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1600792/full |
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| author | Charlotte N. Hill Charlotte N. Hill Charlotte N. Hill Charlotte N. Hill Gabriela Maita Gabriela Maita Gabriela Maita Camille Cabrolier Camille Cabrolier Camille Cabrolier Constanza Aros Constanza Aros Ana Maria Vega-Letter Pamela Gonzalez Pamela Gonzalez Alexis M. Kalergis Alexis M. Kalergis Patricia Luz-Crawford Patricia Luz-Crawford Patricia Luz-Crawford Gareth I. Owen Gareth I. Owen |
| author_facet | Charlotte N. Hill Charlotte N. Hill Charlotte N. Hill Charlotte N. Hill Gabriela Maita Gabriela Maita Gabriela Maita Camille Cabrolier Camille Cabrolier Camille Cabrolier Constanza Aros Constanza Aros Ana Maria Vega-Letter Pamela Gonzalez Pamela Gonzalez Alexis M. Kalergis Alexis M. Kalergis Patricia Luz-Crawford Patricia Luz-Crawford Patricia Luz-Crawford Gareth I. Owen Gareth I. Owen |
| author_sort | Charlotte N. Hill |
| collection | DOAJ |
| description | Immune checkpoint inhibitors have significantly advanced the treatment of gastric cancer (GC), yet therapeutic resistance remains common due to the immunosuppressive tumor microenvironment and redundancy among inhibitory checkpoints. Tim-3 (HAVCR2) is an emerging immune checkpoint receptor implicated in tumor immune evasion. However, the role of its ligand, Galectin-9 (Gal-9, LGALS9), in GC pathogenesis and therapy resistance remains poorly understood. We performed bioinformatic analysis of The Cancer Genome Atlas (TCGA) stomach adenocarcinoma (STAD) dataset to assess LGALS9 and HAVCR2 expression and their clinical correlations. We also evaluated associations between LGALS9 expression and immune cell signatures. Functional ex vivo assays were conducted to investigate the effects of Gal-9 on CD8⁺ T cell function and Treg suppressive activity in the context of Tim-3 signaling. Our analysis revealed that both LGALS9 and HAVCR2 are upregulated in gastric tumors and associated with poor patient survival. HAVCR2 expression was significantly higher in invasive adenocarcinomas. LGALS9 expression strongly correlated with signatures of CD8⁺ T cell dysfunction and increased infiltration of regulatory T cells (Tregs). Functionally, Gal-9 promoted Treg suppressive activity and CD8⁺ T cell dysfunction ex vivo through Tim-3 engagement, independently of PD-1 signaling. These findings suggest that Gal-9 contributes to immune evasion in GC by promoting Treg expansion and CD8⁺ T cell exhaustion, potentially driving resistance to anti-PD-1 therapy. We propose circulating Gal-9 as a candidate biomarker of anti-PD-1 resistance and support the rationale for combined blockade of PD-1 and Tim-3 to enhance immunotherapeutic efficacy in GC. |
| format | Article |
| id | doaj-art-55e2ba927aaa44118cc6c30c35a28a96 |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-55e2ba927aaa44118cc6c30c35a28a962025-08-20T02:37:45ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-07-011610.3389/fimmu.2025.16007921600792Galectin-9 and Tim-3 in gastric cancer: a checkpoint axis driving T cell exhaustion and Treg-mediated immunosuppression independently of anti-PD-1 blockadeCharlotte N. Hill0Charlotte N. Hill1Charlotte N. Hill2Charlotte N. Hill3Gabriela Maita4Gabriela Maita5Gabriela Maita6Camille Cabrolier7Camille Cabrolier8Camille Cabrolier9Constanza Aros10Constanza Aros11Ana Maria Vega-Letter12Pamela Gonzalez13Pamela Gonzalez14Alexis M. Kalergis15Alexis M. Kalergis16Patricia Luz-Crawford17Patricia Luz-Crawford18Patricia Luz-Crawford19Gareth I. Owen20Gareth I. Owen21Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago de Chile, ChileMillenium Institute for Immunology and Immunotherapy, Santiago de Chile, ChileLaboratorio de Inmunología, Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago de Chile, ChileCenter of Interventional Medicine for Precision and Advanced Cellular Therapy (IMPACT), Santiago, ChileFacultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago de Chile, ChileMillenium Institute for Immunology and Immunotherapy, Santiago de Chile, ChileLaboratorio de Inmunología, Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago de Chile, ChileFacultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago de Chile, ChileMillenium Institute for Immunology and Immunotherapy, Santiago de Chile, ChileLaboratorio de Inmunología, Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago de Chile, ChileLaboratorio de Inmunología, Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago de Chile, ChileCenter of Interventional Medicine for Precision and Advanced Cellular Therapy (IMPACT), Santiago, ChileEscuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Valparaíso, ChileFacultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago de Chile, ChileMillenium Institute for Immunology and Immunotherapy, Santiago de Chile, ChileFacultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago de Chile, ChileMillenium Institute for Immunology and Immunotherapy, Santiago de Chile, ChileMillenium Institute for Immunology and Immunotherapy, Santiago de Chile, ChileLaboratorio de Inmunología, Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago de Chile, ChileCenter of Interventional Medicine for Precision and Advanced Cellular Therapy (IMPACT), Santiago, ChileFacultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago de Chile, ChileMillenium Institute for Immunology and Immunotherapy, Santiago de Chile, ChileImmune checkpoint inhibitors have significantly advanced the treatment of gastric cancer (GC), yet therapeutic resistance remains common due to the immunosuppressive tumor microenvironment and redundancy among inhibitory checkpoints. Tim-3 (HAVCR2) is an emerging immune checkpoint receptor implicated in tumor immune evasion. However, the role of its ligand, Galectin-9 (Gal-9, LGALS9), in GC pathogenesis and therapy resistance remains poorly understood. We performed bioinformatic analysis of The Cancer Genome Atlas (TCGA) stomach adenocarcinoma (STAD) dataset to assess LGALS9 and HAVCR2 expression and their clinical correlations. We also evaluated associations between LGALS9 expression and immune cell signatures. Functional ex vivo assays were conducted to investigate the effects of Gal-9 on CD8⁺ T cell function and Treg suppressive activity in the context of Tim-3 signaling. Our analysis revealed that both LGALS9 and HAVCR2 are upregulated in gastric tumors and associated with poor patient survival. HAVCR2 expression was significantly higher in invasive adenocarcinomas. LGALS9 expression strongly correlated with signatures of CD8⁺ T cell dysfunction and increased infiltration of regulatory T cells (Tregs). Functionally, Gal-9 promoted Treg suppressive activity and CD8⁺ T cell dysfunction ex vivo through Tim-3 engagement, independently of PD-1 signaling. These findings suggest that Gal-9 contributes to immune evasion in GC by promoting Treg expansion and CD8⁺ T cell exhaustion, potentially driving resistance to anti-PD-1 therapy. We propose circulating Gal-9 as a candidate biomarker of anti-PD-1 resistance and support the rationale for combined blockade of PD-1 and Tim-3 to enhance immunotherapeutic efficacy in GC.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1600792/fullgastric cancerimmune checkpoint blockadegalectin-9TIM-3anti-PD1 |
| spellingShingle | Charlotte N. Hill Charlotte N. Hill Charlotte N. Hill Charlotte N. Hill Gabriela Maita Gabriela Maita Gabriela Maita Camille Cabrolier Camille Cabrolier Camille Cabrolier Constanza Aros Constanza Aros Ana Maria Vega-Letter Pamela Gonzalez Pamela Gonzalez Alexis M. Kalergis Alexis M. Kalergis Patricia Luz-Crawford Patricia Luz-Crawford Patricia Luz-Crawford Gareth I. Owen Gareth I. Owen Galectin-9 and Tim-3 in gastric cancer: a checkpoint axis driving T cell exhaustion and Treg-mediated immunosuppression independently of anti-PD-1 blockade Frontiers in Immunology gastric cancer immune checkpoint blockade galectin-9 TIM-3 anti-PD1 |
| title | Galectin-9 and Tim-3 in gastric cancer: a checkpoint axis driving T cell exhaustion and Treg-mediated immunosuppression independently of anti-PD-1 blockade |
| title_full | Galectin-9 and Tim-3 in gastric cancer: a checkpoint axis driving T cell exhaustion and Treg-mediated immunosuppression independently of anti-PD-1 blockade |
| title_fullStr | Galectin-9 and Tim-3 in gastric cancer: a checkpoint axis driving T cell exhaustion and Treg-mediated immunosuppression independently of anti-PD-1 blockade |
| title_full_unstemmed | Galectin-9 and Tim-3 in gastric cancer: a checkpoint axis driving T cell exhaustion and Treg-mediated immunosuppression independently of anti-PD-1 blockade |
| title_short | Galectin-9 and Tim-3 in gastric cancer: a checkpoint axis driving T cell exhaustion and Treg-mediated immunosuppression independently of anti-PD-1 blockade |
| title_sort | galectin 9 and tim 3 in gastric cancer a checkpoint axis driving t cell exhaustion and treg mediated immunosuppression independently of anti pd 1 blockade |
| topic | gastric cancer immune checkpoint blockade galectin-9 TIM-3 anti-PD1 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1600792/full |
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