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| Natura: | Artículo científico |
| Lingua: | en |
| Pubblicazione: |
Cancer discovery
2025
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| Soggetti: | |
| Accesso online: | https://pubmed.ncbi.nlm.nih.gov/40530506/ |
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| _version_ | 1868266191316844545 |
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| author | Song, No-Joon Xie, Juan Jung, Kyeong Joo Wang, Yi Pozniak, Joanna Roda, Niccolo Marine, Jean-Christophe Riesenberg, Brian P Jeon, Hyeongseon Ma, Anjun Cox, Nathanael Wethington, Darren Reynolds, Kelsi Xiao, Tong Li, Anqi Kronen, Parker Denko, Nicholas Carbone, David P Ma, Qin Carson, William E Mundy-Bosse, Bethany L Burd, Christin E Das, Jayajit Chung, Dongjun Li, Zihai |
| author_facet | Song, No-Joon Xie, Juan Jung, Kyeong Joo Wang, Yi Pozniak, Joanna Roda, Niccolo Marine, Jean-Christophe Riesenberg, Brian P Jeon, Hyeongseon Ma, Anjun Cox, Nathanael Wethington, Darren Reynolds, Kelsi Xiao, Tong Li, Anqi Kronen, Parker Denko, Nicholas Carbone, David P Ma, Qin Carson, William E Mundy-Bosse, Bethany L Burd, Christin E Das, Jayajit Chung, Dongjun Li, Zihai Song, No-Joon Xie, Juan Jung, Kyeong Joo Wang, Yi Pozniak, Joanna Roda, Niccolo Marine, Jean-Christophe Riesenberg, Brian P Jeon, Hyeongseon Ma, Anjun Cox, Nathanael Wethington, Darren Reynolds, Kelsi Xiao, Tong Li, Anqi Kronen, Parker Denko, Nicholas Carbone, David P Ma, Qin Carson, William E Mundy-Bosse, Bethany L Burd, Christin E Das, Jayajit Chung, Dongjun Li, Zihai |
| collection | PubMed - marine biology |
| contents | Tumor-associated NK Cells Regulate Distinct CD8+ T-cell Differentiation Program in Cancer and Contribute to Resistance against Immune Checkpoint Blockers. Song, No-Joon Xie, Juan Jung, Kyeong Joo Wang, Yi Pozniak, Joanna Roda, Niccolo Marine, Jean-Christophe Riesenberg, Brian P Jeon, Hyeongseon Ma, Anjun Cox, Nathanael Wethington, Darren Reynolds, Kelsi Xiao, Tong Li, Anqi Kronen, Parker Denko, Nicholas Carbone, David P Ma, Qin Carson, William E Mundy-Bosse, Bethany L Burd, Christin E Das, Jayajit Chung, Dongjun Li, Zihai Humans CD8-Positive T-Lymphocytes Immune Checkpoint Inhibitors Killer Cells, Natural Cell Differentiation Mice Neoplasms Animals Drug Resistance, Neoplasm Tumor Microenvironment Immune checkpoint blockers (ICB) targeting the PD-1/PD-L1 axis represent established therapies for many cancers. However, resistance occurs in most patients due to complex immune-suppressive mechanisms in the tumor microenvironment. NK cells can play effector roles in tumor control, but their impact on T-cell dysfunction and ICB efficacy remains controversial. Through genetic and antibody-mediated NK cell depletion, we found that a subset of tumor-associated NK cells plays a negative role in ICB sensitivity; they further impede CD8+ T-cell differentiation toward a CD69+ BCL2+ EOMES+ GZMB+ TIM3- GITR- phenotype. Mechanistically, the retinoic acid receptor α-dependent differentiation program in CD8+ T cells is hindered by tumor-infiltrating NK cells via competition for IFNα and IL-2. Finally, we observed that lower frequencies of NK cells correlate with better clinical responses to ICBs in patients with cancer. These findings suggest potential avenues for enhancing CD8+ T cell-centered immunotherapy by targeting regulatory NK cells. Although NK cells are traditionally viewed as antitumor effectors, our study uncovers their unexpected suppressive role in CD8+ T cell-based immunotherapy. By competing for cytokines, they disrupt retinoic acid receptor α-driven CD8+ T-cell differentiation and limit ICB efficacy. Clinically, reduced NK cell presence is associated with an enhanced immunotherapy response. See related commentary by Galvez-Cancino et al., p. 1777 See related article by Pozniak et al., p. 1819. |
| format | Artículo científico |
| id | pubmed_40530506 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Cancer discovery |
| record_format | pubmed |
| spellingShingle | Tumor-associated NK Cells Regulate Distinct CD8+ T-cell Differentiation Program in Cancer and Contribute to Resistance against Immune Checkpoint Blockers. Song, No-Joon Xie, Juan Jung, Kyeong Joo Wang, Yi Pozniak, Joanna Roda, Niccolo Marine, Jean-Christophe Riesenberg, Brian P Jeon, Hyeongseon Ma, Anjun Cox, Nathanael Wethington, Darren Reynolds, Kelsi Xiao, Tong Li, Anqi Kronen, Parker Denko, Nicholas Carbone, David P Ma, Qin Carson, William E Mundy-Bosse, Bethany L Burd, Christin E Das, Jayajit Chung, Dongjun Li, Zihai Humans CD8-Positive T-Lymphocytes Immune Checkpoint Inhibitors Killer Cells, Natural Cell Differentiation Mice Neoplasms Animals Drug Resistance, Neoplasm Tumor Microenvironment Tumor-associated NK Cells Regulate Distinct CD8+ T-cell Differentiation Program in Cancer and Contribute to Resistance against Immune Checkpoint Blockers. Song, No-Joon Xie, Juan Jung, Kyeong Joo Wang, Yi Pozniak, Joanna Roda, Niccolo Marine, Jean-Christophe Riesenberg, Brian P Jeon, Hyeongseon Ma, Anjun Cox, Nathanael Wethington, Darren Reynolds, Kelsi Xiao, Tong Li, Anqi Kronen, Parker Denko, Nicholas Carbone, David P Ma, Qin Carson, William E Mundy-Bosse, Bethany L Burd, Christin E Das, Jayajit Chung, Dongjun Li, Zihai Humans CD8-Positive T-Lymphocytes Immune Checkpoint Inhibitors Killer Cells, Natural Cell Differentiation Mice Neoplasms Animals Drug Resistance, Neoplasm Tumor Microenvironment Immune checkpoint blockers (ICB) targeting the PD-1/PD-L1 axis represent established therapies for many cancers. However, resistance occurs in most patients due to complex immune-suppressive mechanisms in the tumor microenvironment. NK cells can play effector roles in tumor control, but their impact on T-cell dysfunction and ICB efficacy remains controversial. Through genetic and antibody-mediated NK cell depletion, we found that a subset of tumor-associated NK cells plays a negative role in ICB sensitivity; they further impede CD8+ T-cell differentiation toward a CD69+ BCL2+ EOMES+ GZMB+ TIM3- GITR- phenotype. Mechanistically, the retinoic acid receptor α-dependent differentiation program in CD8+ T cells is hindered by tumor-infiltrating NK cells via competition for IFNα and IL-2. Finally, we observed that lower frequencies of NK cells correlate with better clinical responses to ICBs in patients with cancer. These findings suggest potential avenues for enhancing CD8+ T cell-centered immunotherapy by targeting regulatory NK cells. Although NK cells are traditionally viewed as antitumor effectors, our study uncovers their unexpected suppressive role in CD8+ T cell-based immunotherapy. By competing for cytokines, they disrupt retinoic acid receptor α-driven CD8+ T-cell differentiation and limit ICB efficacy. Clinically, reduced NK cell presence is associated with an enhanced immunotherapy response. See related commentary by Galvez-Cancino et al., p. 1777 See related article by Pozniak et al., p. 1819. |
| title | Tumor-associated NK Cells Regulate Distinct CD8+ T-cell Differentiation Program in Cancer and Contribute to Resistance against Immune Checkpoint Blockers. |
| topic | Humans CD8-Positive T-Lymphocytes Immune Checkpoint Inhibitors Killer Cells, Natural Cell Differentiation Mice Neoplasms Animals Drug Resistance, Neoplasm Tumor Microenvironment |
| url | https://pubmed.ncbi.nlm.nih.gov/40530506/ |