EBV+ tumors exploit tumor cell-intrinsic and -extrinsic mechanisms to produce regulatory T cell-recruiting chemokines CCL17 and CCL22.
The Epstein-Barr Virus (EBV) is involved in the etiology of multiple hematologic and epithelial human cancers. EBV+ tumors employ multiple immune escape mechanisms, including the recruitment of immunosuppressive regulatory T cells (Treg). Here, we show some EBV+ tumor cells express high levels of th...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-01-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1010200 |
| _version_ | 1818329480346730496 |
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| author | Aparna Jorapur Lisa A Marshall Scott Jacobson Mengshu Xu Sachie Marubayashi Mikhail Zibinsky Dennis X Hu Omar Robles Jeffrey J Jackson Valentin Baloche Pierre Busson David Wustrow Dirk G Brockstedt Oezcan Talay Paul D Kassner Gene Cutler |
| author_facet | Aparna Jorapur Lisa A Marshall Scott Jacobson Mengshu Xu Sachie Marubayashi Mikhail Zibinsky Dennis X Hu Omar Robles Jeffrey J Jackson Valentin Baloche Pierre Busson David Wustrow Dirk G Brockstedt Oezcan Talay Paul D Kassner Gene Cutler |
| author_sort | Aparna Jorapur |
| collection | DOAJ |
| description | The Epstein-Barr Virus (EBV) is involved in the etiology of multiple hematologic and epithelial human cancers. EBV+ tumors employ multiple immune escape mechanisms, including the recruitment of immunosuppressive regulatory T cells (Treg). Here, we show some EBV+ tumor cells express high levels of the chemokines CCL17 and CCL22 both in vitro and in vivo and that this expression mirrors the expression levels of expression of the EBV LMP1 gene in vitro. Patient samples from lymphoblastic (Hodgkin lymphoma) and epithelial (nasopharyngeal carcinoma; NPC) EBV+ tumors revealed CCL17 and CCL22 expression of both tumor cell-intrinsic and -extrinsic origin, depending on tumor type. NPCs grown as mouse xenografts likewise showed both mechanisms of chemokine production. Single cell RNA-sequencing revealed in vivo tumor cell-intrinsic CCL17 and CCL22 expression combined with expression from infiltrating classical resident and migratory dendritic cells in a CT26 colon cancer mouse tumor engineered to express LMP1. These data suggest that EBV-driven tumors employ dual mechanisms for CCL17 and CCL22 production. Importantly, both in vitro and in vivo Treg migration was effectively blocked by a novel, small molecule antagonist of CCR4, CCR4-351. Antagonism of the CCR4 receptor may thus be an effective means of activating the immune response against a wide spectrum of EBV+ tumors. |
| first_indexed | 2024-12-13T12:48:44Z |
| format | Article |
| id | doaj.art-4d16e0321b6e41c7ae448e91efe27eef |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-13T12:48:44Z |
| publishDate | 2022-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-4d16e0321b6e41c7ae448e91efe27eef2022-12-21T23:45:24ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742022-01-01181e101020010.1371/journal.ppat.1010200EBV+ tumors exploit tumor cell-intrinsic and -extrinsic mechanisms to produce regulatory T cell-recruiting chemokines CCL17 and CCL22.Aparna JorapurLisa A MarshallScott JacobsonMengshu XuSachie MarubayashiMikhail ZibinskyDennis X HuOmar RoblesJeffrey J JacksonValentin BalochePierre BussonDavid WustrowDirk G BrockstedtOezcan TalayPaul D KassnerGene CutlerThe Epstein-Barr Virus (EBV) is involved in the etiology of multiple hematologic and epithelial human cancers. EBV+ tumors employ multiple immune escape mechanisms, including the recruitment of immunosuppressive regulatory T cells (Treg). Here, we show some EBV+ tumor cells express high levels of the chemokines CCL17 and CCL22 both in vitro and in vivo and that this expression mirrors the expression levels of expression of the EBV LMP1 gene in vitro. Patient samples from lymphoblastic (Hodgkin lymphoma) and epithelial (nasopharyngeal carcinoma; NPC) EBV+ tumors revealed CCL17 and CCL22 expression of both tumor cell-intrinsic and -extrinsic origin, depending on tumor type. NPCs grown as mouse xenografts likewise showed both mechanisms of chemokine production. Single cell RNA-sequencing revealed in vivo tumor cell-intrinsic CCL17 and CCL22 expression combined with expression from infiltrating classical resident and migratory dendritic cells in a CT26 colon cancer mouse tumor engineered to express LMP1. These data suggest that EBV-driven tumors employ dual mechanisms for CCL17 and CCL22 production. Importantly, both in vitro and in vivo Treg migration was effectively blocked by a novel, small molecule antagonist of CCR4, CCR4-351. Antagonism of the CCR4 receptor may thus be an effective means of activating the immune response against a wide spectrum of EBV+ tumors.https://doi.org/10.1371/journal.ppat.1010200 |
| spellingShingle | Aparna Jorapur Lisa A Marshall Scott Jacobson Mengshu Xu Sachie Marubayashi Mikhail Zibinsky Dennis X Hu Omar Robles Jeffrey J Jackson Valentin Baloche Pierre Busson David Wustrow Dirk G Brockstedt Oezcan Talay Paul D Kassner Gene Cutler EBV+ tumors exploit tumor cell-intrinsic and -extrinsic mechanisms to produce regulatory T cell-recruiting chemokines CCL17 and CCL22. PLoS Pathogens |
| title | EBV+ tumors exploit tumor cell-intrinsic and -extrinsic mechanisms to produce regulatory T cell-recruiting chemokines CCL17 and CCL22. |
| title_full | EBV+ tumors exploit tumor cell-intrinsic and -extrinsic mechanisms to produce regulatory T cell-recruiting chemokines CCL17 and CCL22. |
| title_fullStr | EBV+ tumors exploit tumor cell-intrinsic and -extrinsic mechanisms to produce regulatory T cell-recruiting chemokines CCL17 and CCL22. |
| title_full_unstemmed | EBV+ tumors exploit tumor cell-intrinsic and -extrinsic mechanisms to produce regulatory T cell-recruiting chemokines CCL17 and CCL22. |
| title_short | EBV+ tumors exploit tumor cell-intrinsic and -extrinsic mechanisms to produce regulatory T cell-recruiting chemokines CCL17 and CCL22. |
| title_sort | ebv tumors exploit tumor cell intrinsic and extrinsic mechanisms to produce regulatory t cell recruiting chemokines ccl17 and ccl22 |
| url | https://doi.org/10.1371/journal.ppat.1010200 |
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