| 1. |
- Hartana, C. A., et al.
(författare)
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Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer
- 2018
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Ingår i: Clinical and Experimental Immunology. - : WILEY. - 0009-9104 .- 1365-2249. ; 194:1, s. 39-53
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Tidskriftsartikel (refereegranskat)abstract
- Tissue-resident memory T (T-RM) cells are CD8(+) T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in T-RM cells and correlate it with their functional potential. Fifty-three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in T-RM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in-vitro stimulation were used to evaluate T-RM cell phenotypes. We discovered that tumour T-RM cells have low DNA methylation in the PRF1 locus (329% methylation), which corresponds to increased numbers of perforin-expressing T-RM cells. Surprisingly, programmed cell death 1 (PD-1) expression is high in tumour T-RM cells, suggesting exhaustion. Following interleukin-15 and T cell receptor stimulation, perforin and T-bet expressions are enhanced, indicating that T-RM cells from tumours are not terminally exhausted. Moreover, a high number of T-RM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, T-RM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies T-RM cells as potential new targets for cancer immunotherapy.
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| 2. |
- Hu, J., et al.
(författare)
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The effects of chemotherapeutic drugs on human monocyte-derived dendritic cell differentiation and antigen presentation
- 2013
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 172:3, s. 490-499
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies indicate that chemotherapeutic agents may increase the anti-tumoral immune response. Based on the pivotal role of dendritic cells (DCs) in host tumour-specific immune responses, we investigated the effect of commonly used chemotherapeutic drugs dexamethasone, doxorubicin, cisplatin and irinotecan and glucocorticoids on monocyte-derived DCs (moDCs). Dexamethasone displayed the strongest inhibitory effect on DC differentiation. The effect of cisplatin and irinotecan was moderate, while only weak effects were noticed for doxorubicin. Surprisingly, when the functional consequence of chemotherapy-treated CD14+ monocytes and their capacity to activate CD4+ T responders cells were investigated, cisplatin-treated monocytes gave rise to increased T cell proliferation. However, dexamethasone, doxorubicin and irinotecan-pretreated monocytes did not stimulate any increased T cell proliferation. Further investigation of this observation revealed that cisplatin treatment during DC differentiation up-regulated significantly the interferon (IFN)- transcript. By contrast, no effect was evident on the expression of interleukin (IL)-1, tumour necrosis factor (TNF)-, IL-6 or IFN- transcripts. Blocking IFN- attenuated the cisplatin-enhanced T cell proliferation significantly. In conclusion, cisplatin treatment enhanced the immune stimulatory ability of human monocytes, a mechanism mediated mainly by the increased production of IFN-.
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| 3. |
- Sherif, Amir, et al.
(författare)
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Sentinel lymph node detection in urinary bladder cancer : a gateway to advanced translational research and cellular immunotherapy Minireview
- 2016
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Ingår i: Egyptian Journal Of Urology. - 1110-5712. ; 22, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- Patients with advanced urothelial urinary bladder cancer (UBC) have a pessimistic prognosis, although modern urology can offer preoperative chemotherapy followed by radical surgery. Attempts to find additional, other than adjuvant cytotoxic treatment options need to be explored. The field of immune therapy may be of particular value in UBC since immunotherapy of superficial UBC using an unspecific immunotherapy modality, namely BCG, has been so successful. In addition, UBC is one of the most genetically unstable cancers carrying many neo-antigens as potential targets for T lymphocyte recognition. A tempting option aiming at highly individualized treatment could be autologous cell therapy based on the concepts of sentinel node detection. The sentinel nodes, representing the foremost arena for the struggle between the immune system of the patient and the tumor assault, can offer high quantities of highly specialized T lymphocytes. These T cells have evolved in response to a number of specific tumor antigens reaching the tumor draining sentinel nodes en route. Adoptive immunotherapy within this framework entails possibilities of harvesting tumor specific T cells from the sentinel nodes and allowing them to expand in vitro. Expanded and strengthened T cells can then be reinfused as a safe and non-toxic adjuvant immunotherapy. The first pilot trials have been published utilizing this method in two solid cancers, colon and UBC. Results demonstrate objective responses in some patients without any negative side effects. The future challenge is to increase the translational research in this specific field, to further improve immunobiological techniques, to optimize patient selection and to perform larger randomized controlled clinical trials.
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