Black raspberry extract inhibits regulatory T-cell activity in a murine model of head and neck squamous cell carcinoma chemoprevention
Head and neck squamous cell carcinomas (HNSCC) are one of the most diagnosed malignancies globally, with a 5-year survival rate of approximately 40% to 50%. Current therapies are limited to highly invasive surgery, aggressive radiation, and chemotherapies. Recent reports have demonstrated the potent...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.932742/full |
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| author | Nathan M. Ryan Felipe F. Lamenza Felipe F. Lamenza Puja Upadhaya Hasan Pracha Anna Springer Michael Swingler Arham Siddiqui Steve Oghumu |
| author_facet | Nathan M. Ryan Felipe F. Lamenza Felipe F. Lamenza Puja Upadhaya Hasan Pracha Anna Springer Michael Swingler Arham Siddiqui Steve Oghumu |
| author_sort | Nathan M. Ryan |
| collection | DOAJ |
| description | Head and neck squamous cell carcinomas (HNSCC) are one of the most diagnosed malignancies globally, with a 5-year survival rate of approximately 40% to 50%. Current therapies are limited to highly invasive surgery, aggressive radiation, and chemotherapies. Recent reports have demonstrated the potential phytochemical properties of black raspberries in inhibiting the progression of various cancers including HNSCCs. However, the effects of black raspberry extracts on immune cells of the tumor microenvironment, specifically regulatory T cells during HNSCC, have not been investigated. We used a mouse model of 4-nitroquinoline-1-oxide (4NQO) chemically induced HNSCC carcinogenesis to determine these effects. C57BL/6 mice were exposed to 4NQO for 16 weeks and regular water for 8 weeks. 4NQO-exposed mice were fed the AIN-76A control mouse diet or the AIN76 diet supplemented with black raspberry extract. At terminal sacrifice, tumor burdens and immune cell recruitment and activity were analyzed in the tumor microenvironment, draining lymph nodes, and spleens. Mice fed the BRB extract-supplemented diet displayed decreased tumor burden compared to mice provided the AIN-76A control diet. Black raspberry extract administration did not affect overall T-cell populations as well as Th1, Th2, or Th17 differentiation in spleens and tumor draining lymph nodes. However, dietary black raspberry extract administration inhibited regulatory T-cell recruitment to HNSCC tumor sites. This was associated with an increased cytotoxic immune response in the tumor microenvironment characterized by increased CD8+ T cells and enhanced Granzyme B production during BRB extract-mediated HNSCC chemoprevention. Interestingly, this enhanced CD8+ T-cell antitumoral response was localized at the tumor sites but not at spleens and draining lymph nodes. Furthermore, we found decreased levels of PD-L1 expression by myeloid populations in draining lymph nodes of black raspberry-administered carcinogen-induced mice. Taken together, our findings demonstrate that black raspberry extract inhibits regulatory T-cell recruitment and promotes cytotoxic CD8 T-cell activity at tumor sites during HNSCC chemoprevention. These results demonstrate the immunomodulatory potential of black raspberry extracts and support the use of black raspberry-derived phytochemicals as a complementary approach to HNSCC chemoprevention and treatment. |
| first_indexed | 2024-12-10T21:39:53Z |
| format | Article |
| id | doaj.art-a72504590b7b4317ac8bec1e2d7c6e0b |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-10T21:39:53Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-a72504590b7b4317ac8bec1e2d7c6e0b2022-12-22T01:32:32ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-08-011310.3389/fimmu.2022.932742932742Black raspberry extract inhibits regulatory T-cell activity in a murine model of head and neck squamous cell carcinoma chemopreventionNathan M. Ryan0Felipe F. Lamenza1Felipe F. Lamenza2Puja Upadhaya3Hasan Pracha4Anna Springer5Michael Swingler6Arham Siddiqui7Steve Oghumu8Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesDepartment of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesDepartment of Microbiology, The Ohio State University, Columbus, OH, United StatesDepartment of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesDepartment of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesDepartment of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesDepartment of Microbiology, Immunology, and Inflammation, Center of Neurovirology and Gene Editing, School of Medicine, Temple University, Philadelphia, PA, United StatesKentucky College of Osteopathic Medicine, University of Pikeville, Pikeville, KY, United StatesDepartment of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United StatesHead and neck squamous cell carcinomas (HNSCC) are one of the most diagnosed malignancies globally, with a 5-year survival rate of approximately 40% to 50%. Current therapies are limited to highly invasive surgery, aggressive radiation, and chemotherapies. Recent reports have demonstrated the potential phytochemical properties of black raspberries in inhibiting the progression of various cancers including HNSCCs. However, the effects of black raspberry extracts on immune cells of the tumor microenvironment, specifically regulatory T cells during HNSCC, have not been investigated. We used a mouse model of 4-nitroquinoline-1-oxide (4NQO) chemically induced HNSCC carcinogenesis to determine these effects. C57BL/6 mice were exposed to 4NQO for 16 weeks and regular water for 8 weeks. 4NQO-exposed mice were fed the AIN-76A control mouse diet or the AIN76 diet supplemented with black raspberry extract. At terminal sacrifice, tumor burdens and immune cell recruitment and activity were analyzed in the tumor microenvironment, draining lymph nodes, and spleens. Mice fed the BRB extract-supplemented diet displayed decreased tumor burden compared to mice provided the AIN-76A control diet. Black raspberry extract administration did not affect overall T-cell populations as well as Th1, Th2, or Th17 differentiation in spleens and tumor draining lymph nodes. However, dietary black raspberry extract administration inhibited regulatory T-cell recruitment to HNSCC tumor sites. This was associated with an increased cytotoxic immune response in the tumor microenvironment characterized by increased CD8+ T cells and enhanced Granzyme B production during BRB extract-mediated HNSCC chemoprevention. Interestingly, this enhanced CD8+ T-cell antitumoral response was localized at the tumor sites but not at spleens and draining lymph nodes. Furthermore, we found decreased levels of PD-L1 expression by myeloid populations in draining lymph nodes of black raspberry-administered carcinogen-induced mice. Taken together, our findings demonstrate that black raspberry extract inhibits regulatory T-cell recruitment and promotes cytotoxic CD8 T-cell activity at tumor sites during HNSCC chemoprevention. These results demonstrate the immunomodulatory potential of black raspberry extracts and support the use of black raspberry-derived phytochemicals as a complementary approach to HNSCC chemoprevention and treatment.https://www.frontiersin.org/articles/10.3389/fimmu.2022.932742/fullblack raspberries (Rubus occidentalis)HNSCC (head and neck squamous cell carcinoma)Treg - regulatory T cellchemopreventionT cellimmunomodulation |
| spellingShingle | Nathan M. Ryan Felipe F. Lamenza Felipe F. Lamenza Puja Upadhaya Hasan Pracha Anna Springer Michael Swingler Arham Siddiqui Steve Oghumu Black raspberry extract inhibits regulatory T-cell activity in a murine model of head and neck squamous cell carcinoma chemoprevention Frontiers in Immunology black raspberries (Rubus occidentalis) HNSCC (head and neck squamous cell carcinoma) Treg - regulatory T cell chemoprevention T cell immunomodulation |
| title | Black raspberry extract inhibits regulatory T-cell activity in a murine model of head and neck squamous cell carcinoma chemoprevention |
| title_full | Black raspberry extract inhibits regulatory T-cell activity in a murine model of head and neck squamous cell carcinoma chemoprevention |
| title_fullStr | Black raspberry extract inhibits regulatory T-cell activity in a murine model of head and neck squamous cell carcinoma chemoprevention |
| title_full_unstemmed | Black raspberry extract inhibits regulatory T-cell activity in a murine model of head and neck squamous cell carcinoma chemoprevention |
| title_short | Black raspberry extract inhibits regulatory T-cell activity in a murine model of head and neck squamous cell carcinoma chemoprevention |
| title_sort | black raspberry extract inhibits regulatory t cell activity in a murine model of head and neck squamous cell carcinoma chemoprevention |
| topic | black raspberries (Rubus occidentalis) HNSCC (head and neck squamous cell carcinoma) Treg - regulatory T cell chemoprevention T cell immunomodulation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.932742/full |
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