Chemotherapy accelerates immune-senescence and functional impairments of Vδ2pos T cells in elderly patients affected by liver metastatic colorectal cancer
Abstract Human (gamma delta) γδ T cells are unconventional innate-like lymphocytes displaying a broad array of anti-tumor activities with promising perspectives in cancer immunotherapy. In this context, Vδ2pos T cells represent the preferential target of several immunotherapy protocols against solid...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2019-12-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0825-4 |
| _version_ | 1819080810706239488 |
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| author | Elena Bruni Valentina Cazzetta Matteo Donadon Matteo Cimino Guido Torzilli Gianmarco Spata Gloria Leonardi Francesco Dieli Joanna Mikulak Domenico Mavilio |
| author_facet | Elena Bruni Valentina Cazzetta Matteo Donadon Matteo Cimino Guido Torzilli Gianmarco Spata Gloria Leonardi Francesco Dieli Joanna Mikulak Domenico Mavilio |
| author_sort | Elena Bruni |
| collection | DOAJ |
| description | Abstract Human (gamma delta) γδ T cells are unconventional innate-like lymphocytes displaying a broad array of anti-tumor activities with promising perspectives in cancer immunotherapy. In this context, Vδ2pos T cells represent the preferential target of several immunotherapy protocols against solid tumors. However, the impact of both aging and chemotherapy (CHT) on Vδ2pos T cells is still unknown. The present study evaluates with multi-parametric flow cytometry the frequencies, terminal differentiation, senescence and effector-functions of peripheral blood and tumor infiltrating Vδ2pos T cells purified from liver metastases (CLM) of patients affected by colorectal cancer (CRC) compared to those of sex- and age-matched healthy donors. The peripheral blood of CLM patients underwent CHT is characterized by decreased amounts of Vδ2pos T cells showing a relative increase of terminally-differentiated CD27neg/CD45RApos (TEMRA) cells. The enrichment of this latter subset is associated with an increased expression of the senescent marker CD57. The acquisition of CD57 on TEMRA Vδ2pos T cells is also coupled with impairments in cytotoxicity and production of TNF-α and IFN-γ. These features resemble the acquisition of an immune-senescent profile by Vδ2pos T cells from CLM patients that received CHT, a phenomenon that is also associated with the loss of the co-stimulatory marker CD28 and with the induced expression of CD16. The group of CLM patients underwent CHT and older than 60 years old showed higher frequencies of CD57pos and TEMRA Vδ2pos T cells. Similar results were found for tumor infiltrating Vδ2pos T cell subset purified from CLM specimens of patients treated with CHT. The toxicity of CHT regimens also affects the homeostasis of Vδ2pos T cells by inducing higher frequencies of circulating CD57pos TEMRA subset in CLM underwent CHT and younger than 60 years old. Taken together, our data demonstrate that the enrichment of senescent Vδ2pos T cells in CLM patients is not only induced by patients’ aging but also by the toxicity of CHT that further accelerates the accumulation of CD57pos TEMRA cells highly dysfunctional in their anti-tumor activities. These results are important to both predict the clinical outcome of CLM and to optimize those protocols of cell cancer immunotherapy employing unconventional Vδ2pos T cells. |
| first_indexed | 2024-12-21T19:50:48Z |
| format | Article |
| id | doaj.art-90283269ab214e1b9f32c60c6481d39b |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-21T19:50:48Z |
| publishDate | 2019-12-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-90283269ab214e1b9f32c60c6481d39b2022-12-21T18:52:13ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-12-01711810.1186/s40425-019-0825-4Chemotherapy accelerates immune-senescence and functional impairments of Vδ2pos T cells in elderly patients affected by liver metastatic colorectal cancerElena Bruni0Valentina Cazzetta1Matteo Donadon2Matteo Cimino3Guido Torzilli4Gianmarco Spata5Gloria Leonardi6Francesco Dieli7Joanna Mikulak8Domenico Mavilio9Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center – IRCCSUnit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center – IRCCSDepartment of Hepatobiliary and General Surgery, Humanitas University, Humanitas Clinical and Research Center – IRCCSDepartment of Hepatobiliary and General Surgery, Humanitas University, Humanitas Clinical and Research Center – IRCCSDepartment of Hepatobiliary and General Surgery, Humanitas University, Humanitas Clinical and Research Center – IRCCSUnit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center – IRCCSUnit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center – IRCCSCentral Laboratory for Advanced Diagnosis and Biomedical ResearchUnit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center – IRCCSUnit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center – IRCCSAbstract Human (gamma delta) γδ T cells are unconventional innate-like lymphocytes displaying a broad array of anti-tumor activities with promising perspectives in cancer immunotherapy. In this context, Vδ2pos T cells represent the preferential target of several immunotherapy protocols against solid tumors. However, the impact of both aging and chemotherapy (CHT) on Vδ2pos T cells is still unknown. The present study evaluates with multi-parametric flow cytometry the frequencies, terminal differentiation, senescence and effector-functions of peripheral blood and tumor infiltrating Vδ2pos T cells purified from liver metastases (CLM) of patients affected by colorectal cancer (CRC) compared to those of sex- and age-matched healthy donors. The peripheral blood of CLM patients underwent CHT is characterized by decreased amounts of Vδ2pos T cells showing a relative increase of terminally-differentiated CD27neg/CD45RApos (TEMRA) cells. The enrichment of this latter subset is associated with an increased expression of the senescent marker CD57. The acquisition of CD57 on TEMRA Vδ2pos T cells is also coupled with impairments in cytotoxicity and production of TNF-α and IFN-γ. These features resemble the acquisition of an immune-senescent profile by Vδ2pos T cells from CLM patients that received CHT, a phenomenon that is also associated with the loss of the co-stimulatory marker CD28 and with the induced expression of CD16. The group of CLM patients underwent CHT and older than 60 years old showed higher frequencies of CD57pos and TEMRA Vδ2pos T cells. Similar results were found for tumor infiltrating Vδ2pos T cell subset purified from CLM specimens of patients treated with CHT. The toxicity of CHT regimens also affects the homeostasis of Vδ2pos T cells by inducing higher frequencies of circulating CD57pos TEMRA subset in CLM underwent CHT and younger than 60 years old. Taken together, our data demonstrate that the enrichment of senescent Vδ2pos T cells in CLM patients is not only induced by patients’ aging but also by the toxicity of CHT that further accelerates the accumulation of CD57pos TEMRA cells highly dysfunctional in their anti-tumor activities. These results are important to both predict the clinical outcome of CLM and to optimize those protocols of cell cancer immunotherapy employing unconventional Vδ2pos T cells.http://link.springer.com/article/10.1186/s40425-019-0825-4γδ T cellsImmune-senescence/AgingCancerChemotherapy |
| spellingShingle | Elena Bruni Valentina Cazzetta Matteo Donadon Matteo Cimino Guido Torzilli Gianmarco Spata Gloria Leonardi Francesco Dieli Joanna Mikulak Domenico Mavilio Chemotherapy accelerates immune-senescence and functional impairments of Vδ2pos T cells in elderly patients affected by liver metastatic colorectal cancer Journal for ImmunoTherapy of Cancer γδ T cells Immune-senescence/Aging Cancer Chemotherapy |
| title | Chemotherapy accelerates immune-senescence and functional impairments of Vδ2pos T cells in elderly patients affected by liver metastatic colorectal cancer |
| title_full | Chemotherapy accelerates immune-senescence and functional impairments of Vδ2pos T cells in elderly patients affected by liver metastatic colorectal cancer |
| title_fullStr | Chemotherapy accelerates immune-senescence and functional impairments of Vδ2pos T cells in elderly patients affected by liver metastatic colorectal cancer |
| title_full_unstemmed | Chemotherapy accelerates immune-senescence and functional impairments of Vδ2pos T cells in elderly patients affected by liver metastatic colorectal cancer |
| title_short | Chemotherapy accelerates immune-senescence and functional impairments of Vδ2pos T cells in elderly patients affected by liver metastatic colorectal cancer |
| title_sort | chemotherapy accelerates immune senescence and functional impairments of vδ2pos t cells in elderly patients affected by liver metastatic colorectal cancer |
| topic | γδ T cells Immune-senescence/Aging Cancer Chemotherapy |
| url | http://link.springer.com/article/10.1186/s40425-019-0825-4 |
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