Differential impact of TIM-3 ligands on NK cell function
Background The transmembrane protein T-cell immunoglobulin and mucin-domain containing molecule 3 (TIM-3) is an immune checkpoint receptor that is expressed by a variety of leukocyte subsets, particularly in the tumor microenvironment. An effective TIM-3-targeting therapy should account for multiple...
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BMJ Publishing Group
2025-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/1/e010618.full |
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| author | Xin Zhang Lazar Vujanovic Riyue Bao Robert L Ferris Tullia C Bruno Aditi Kulkarni Hridesh Banerjee Housaiyin Li Juncheng Wang Lawrence P Kane Pragati Upadhyay Jennifer L Anderson Onyedikachi Victor Onyekachi Lidia M R B Arantes |
| author_facet | Xin Zhang Lazar Vujanovic Riyue Bao Robert L Ferris Tullia C Bruno Aditi Kulkarni Hridesh Banerjee Housaiyin Li Juncheng Wang Lawrence P Kane Pragati Upadhyay Jennifer L Anderson Onyedikachi Victor Onyekachi Lidia M R B Arantes |
| author_sort | Xin Zhang |
| collection | DOAJ |
| description | Background The transmembrane protein T-cell immunoglobulin and mucin-domain containing molecule 3 (TIM-3) is an immune checkpoint receptor that is expressed by a variety of leukocyte subsets, particularly in the tumor microenvironment. An effective TIM-3-targeting therapy should account for multiple biological factors, including the disease setting, the specific cell types involved and their varying sensitivities to the four putative TIM-3 ligands (galectin-9, phosphatidylserine, high mobility group protein B1 and carcinoembryonic antigen cell adhesion molecule 1), each of which engages a unique binding site on the receptor’s variable immunoglobulin domain. The primary objectives of this study were to assess the prevalence and function of TIM-3+ natural killer (NK) cells in patients with head and neck squamous cell carcinoma (HNSCC), determine whether the four TIM-3 ligands differentially affect TIM-3+ NK cell functions, identify the most immunosuppressive ligand, and evaluate whether targeting ligand-mediated TIM-3 signaling enhances NK cell effector functions.Methods Single-cell RNA sequencing and flow cytometry were used to study the prevalence, phenotypes and function of TIM-3+ NK cells in HNSCC patient tumors and blood. In vitro killing, proliferation and cytokine production assays were implemented to evaluate whether the four TIM-3 ligands differentially modulate TIM-3+ NK cell functions, and whether disruption of TIM-3/ligand interaction can enhance NK cell-mediated antitumor effector mechanisms. Finally, The Cancer Genome Atlas survival analysis and digital spatial profiling were employed to study the potential impact of etiology-associated differences on patients with HNSCC outcomes.Results We demonstrate that TIM-3 is highly prevalent on circulating and tumor-infiltrating NK cells. It co-expresses with CD44 and marks NK cells with heightened effector potential. Among the four putative TIM-3 ligands, galectin-9 most consistently suppresses NK cell-mediated cytotoxicity and proliferation through TIM-3 and CD44 signaling, respectively, but promotes IFN-γ release in a TIM-3-dependent manner. Among patients with HNSCC, an elevated intratumoral TIM-3+ NK cell gene signature associates with worse outcomes, specifically in those with human papillomavirus (HPV)+ disease, potentially attributable to higher galectin-9 levels in HPV+ versus HPV− patients.Conclusions Our findings underscore the complex functional impact of TIM-3 ligand signaling, which is consistent with recent clinical trials suggesting that targeting TIM-3 alone is suboptimal as an immunotherapeutic approach for treating malignancies. |
| format | Article |
| id | doaj-art-bcf9cde990084ed29b439796c3df3872 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-bcf9cde990084ed29b439796c3df38722025-01-09T17:35:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-01-0113110.1136/jitc-2024-010618Differential impact of TIM-3 ligands on NK cell functionXin Zhang0Lazar Vujanovic1Riyue Bao2Robert L Ferris3Tullia C Bruno4Aditi Kulkarni5Hridesh Banerjee6Housaiyin Li7Juncheng Wang8Lawrence P Kane9Pragati Upadhyay10Jennifer L Anderson11Onyedikachi Victor Onyekachi12Lidia M R B Arantes13Otolaryngology Head and Neck Surgery, Central South University, Changsha, Hunan, ChinaOtolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USAUPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USAUNC Lineberger Comprehensive Cancer Center, UNC Health Care System, Chapel Hill, North Carolina, USAUPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USAOtolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USAImmunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USAUPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USAOtolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USAImmunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USAOtolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USAOtolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USAUPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USAUPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USABackground The transmembrane protein T-cell immunoglobulin and mucin-domain containing molecule 3 (TIM-3) is an immune checkpoint receptor that is expressed by a variety of leukocyte subsets, particularly in the tumor microenvironment. An effective TIM-3-targeting therapy should account for multiple biological factors, including the disease setting, the specific cell types involved and their varying sensitivities to the four putative TIM-3 ligands (galectin-9, phosphatidylserine, high mobility group protein B1 and carcinoembryonic antigen cell adhesion molecule 1), each of which engages a unique binding site on the receptor’s variable immunoglobulin domain. The primary objectives of this study were to assess the prevalence and function of TIM-3+ natural killer (NK) cells in patients with head and neck squamous cell carcinoma (HNSCC), determine whether the four TIM-3 ligands differentially affect TIM-3+ NK cell functions, identify the most immunosuppressive ligand, and evaluate whether targeting ligand-mediated TIM-3 signaling enhances NK cell effector functions.Methods Single-cell RNA sequencing and flow cytometry were used to study the prevalence, phenotypes and function of TIM-3+ NK cells in HNSCC patient tumors and blood. In vitro killing, proliferation and cytokine production assays were implemented to evaluate whether the four TIM-3 ligands differentially modulate TIM-3+ NK cell functions, and whether disruption of TIM-3/ligand interaction can enhance NK cell-mediated antitumor effector mechanisms. Finally, The Cancer Genome Atlas survival analysis and digital spatial profiling were employed to study the potential impact of etiology-associated differences on patients with HNSCC outcomes.Results We demonstrate that TIM-3 is highly prevalent on circulating and tumor-infiltrating NK cells. It co-expresses with CD44 and marks NK cells with heightened effector potential. Among the four putative TIM-3 ligands, galectin-9 most consistently suppresses NK cell-mediated cytotoxicity and proliferation through TIM-3 and CD44 signaling, respectively, but promotes IFN-γ release in a TIM-3-dependent manner. Among patients with HNSCC, an elevated intratumoral TIM-3+ NK cell gene signature associates with worse outcomes, specifically in those with human papillomavirus (HPV)+ disease, potentially attributable to higher galectin-9 levels in HPV+ versus HPV− patients.Conclusions Our findings underscore the complex functional impact of TIM-3 ligand signaling, which is consistent with recent clinical trials suggesting that targeting TIM-3 alone is suboptimal as an immunotherapeutic approach for treating malignancies.https://jitc.bmj.com/content/13/1/e010618.full |
| spellingShingle | Xin Zhang Lazar Vujanovic Riyue Bao Robert L Ferris Tullia C Bruno Aditi Kulkarni Hridesh Banerjee Housaiyin Li Juncheng Wang Lawrence P Kane Pragati Upadhyay Jennifer L Anderson Onyedikachi Victor Onyekachi Lidia M R B Arantes Differential impact of TIM-3 ligands on NK cell function Journal for ImmunoTherapy of Cancer |
| title | Differential impact of TIM-3 ligands on NK cell function |
| title_full | Differential impact of TIM-3 ligands on NK cell function |
| title_fullStr | Differential impact of TIM-3 ligands on NK cell function |
| title_full_unstemmed | Differential impact of TIM-3 ligands on NK cell function |
| title_short | Differential impact of TIM-3 ligands on NK cell function |
| title_sort | differential impact of tim 3 ligands on nk cell function |
| url | https://jitc.bmj.com/content/13/1/e010618.full |
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