Inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancer
Plasmacytoid dendritic cells (pDCs) are the major producers of type I interferons (IFNs), which are essential to mount antiviral and antitumoral immune responses. To avoid exaggerated levels of type I IFNs, which pave the way to immune dysregulation and autoimmunity, pDC activation is strictly regul...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1360291/full |
| _version_ | 1797277148974678016 |
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| author | Laura Tiberio Mattia Laffranchi Giovanni Zucchi Valentina Salvi Tiziana Schioppa Tiziana Schioppa Silvano Sozzani Silvano Sozzani Annalisa Del Prete Annalisa Del Prete Daniela Bosisio |
| author_facet | Laura Tiberio Mattia Laffranchi Giovanni Zucchi Valentina Salvi Tiziana Schioppa Tiziana Schioppa Silvano Sozzani Silvano Sozzani Annalisa Del Prete Annalisa Del Prete Daniela Bosisio |
| author_sort | Laura Tiberio |
| collection | DOAJ |
| description | Plasmacytoid dendritic cells (pDCs) are the major producers of type I interferons (IFNs), which are essential to mount antiviral and antitumoral immune responses. To avoid exaggerated levels of type I IFNs, which pave the way to immune dysregulation and autoimmunity, pDC activation is strictly regulated by a variety of inhibitory receptors (IRs). In tumors, pDCs display an exhausted phenotype and correlate with an unfavorable prognosis, which largely depends on the accumulation of immunosuppressive cytokines and oncometabolites. This review explores the hypothesis that tumor microenvironment may reduce the release of type I IFNs also by a more pDC-specific mechanism, namely the engagement of IRs. Literature shows that many cancer types express de novo, or overexpress, IR ligands (such as BST2, PCNA, CAECAM-1 and modified surface carbohydrates) which often represent a strong predictor of poor outcome and metastasis. In line with this, tumor cells expressing ligands engaging IRs such as BDCA-2, ILT7, TIM3 and CD44 block pDC activation, while this blocking is prevented when IR engagement or signaling is inhibited. Based on this evidence, we propose that the regulation of IFN secretion by IRs may be regarded as an “innate checkpoint”, reminiscent of the function of “classical” adaptive immune checkpoints, like PD1 expressed in CD8+ T cells, which restrain autoimmunity and immunopathology but favor chronic infections and tumors. However, we also point out that further work is needed to fully unravel the biology of tumor-associated pDCs, the neat contribution of pDC exhaustion in tumor growth following the engagement of IRs, especially those expressed also by other leukocytes, and their therapeutic potential as targets of combined immune checkpoint blockade in cancer immunotherapy. |
| first_indexed | 2024-03-07T15:44:28Z |
| format | Article |
| id | doaj.art-61a17ad511344d24b25a060408281951 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-07T15:44:28Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-61a17ad511344d24b25a0604082819512024-03-05T05:02:57ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-03-011510.3389/fimmu.2024.13602911360291Inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancerLaura Tiberio0Mattia Laffranchi1Giovanni Zucchi2Valentina Salvi3Tiziana Schioppa4Tiziana Schioppa5Silvano Sozzani6Silvano Sozzani7Annalisa Del Prete8Annalisa Del Prete9Daniela Bosisio10Department of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Molecular Medicine, Laboratory Affiliated to Institute Pasteur-Italia, Sapienza University of Rome, Rome, ItalyDepartment of Molecular Medicine, Laboratory Affiliated to Institute Pasteur-Italia, Sapienza University of Rome, Rome, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyIRCCS Humanitas Research Hospital, Milan, ItalyDepartment of Molecular Medicine, Laboratory Affiliated to Institute Pasteur-Italia, Sapienza University of Rome, Rome, ItalyIRCCS Neuromed, Pozzilli, IS, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyIRCCS Humanitas Research Hospital, Milan, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyPlasmacytoid dendritic cells (pDCs) are the major producers of type I interferons (IFNs), which are essential to mount antiviral and antitumoral immune responses. To avoid exaggerated levels of type I IFNs, which pave the way to immune dysregulation and autoimmunity, pDC activation is strictly regulated by a variety of inhibitory receptors (IRs). In tumors, pDCs display an exhausted phenotype and correlate with an unfavorable prognosis, which largely depends on the accumulation of immunosuppressive cytokines and oncometabolites. This review explores the hypothesis that tumor microenvironment may reduce the release of type I IFNs also by a more pDC-specific mechanism, namely the engagement of IRs. Literature shows that many cancer types express de novo, or overexpress, IR ligands (such as BST2, PCNA, CAECAM-1 and modified surface carbohydrates) which often represent a strong predictor of poor outcome and metastasis. In line with this, tumor cells expressing ligands engaging IRs such as BDCA-2, ILT7, TIM3 and CD44 block pDC activation, while this blocking is prevented when IR engagement or signaling is inhibited. Based on this evidence, we propose that the regulation of IFN secretion by IRs may be regarded as an “innate checkpoint”, reminiscent of the function of “classical” adaptive immune checkpoints, like PD1 expressed in CD8+ T cells, which restrain autoimmunity and immunopathology but favor chronic infections and tumors. However, we also point out that further work is needed to fully unravel the biology of tumor-associated pDCs, the neat contribution of pDC exhaustion in tumor growth following the engagement of IRs, especially those expressed also by other leukocytes, and their therapeutic potential as targets of combined immune checkpoint blockade in cancer immunotherapy.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1360291/fullBDCA-2ILT7pDC exhaustionC-type lectin receptorTLR7checkpoint inhibitors |
| spellingShingle | Laura Tiberio Mattia Laffranchi Giovanni Zucchi Valentina Salvi Tiziana Schioppa Tiziana Schioppa Silvano Sozzani Silvano Sozzani Annalisa Del Prete Annalisa Del Prete Daniela Bosisio Inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancer Frontiers in Immunology BDCA-2 ILT7 pDC exhaustion C-type lectin receptor TLR7 checkpoint inhibitors |
| title | Inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancer |
| title_full | Inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancer |
| title_fullStr | Inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancer |
| title_full_unstemmed | Inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancer |
| title_short | Inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancer |
| title_sort | inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancer |
| topic | BDCA-2 ILT7 pDC exhaustion C-type lectin receptor TLR7 checkpoint inhibitors |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1360291/full |
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