P08.02 Harnessing T cells to target brain metastasis
| العنوان: | P08.02 Harnessing T cells to target brain metastasis |
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| المؤلفون: | Robert J Salmond, Rebecca J Brownlie, Mihaela Lorger, Tereza Andreou, Christopher Fife, S R Gregory, F James, H Carrasco Hope, J Newton-Bishop, Jennifer Williams |
| المصدر: | Neuro Oncol |
| بيانات النشر: | Oxford University Press (OUP), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, Chemokine, biology, medicine.diagnostic_test, Chemistry, Melanoma, medicine.disease, Flow cytometry, Poster Presentations, Chemokine receptor, Cytokine release syndrome, Oncology, Apoptosis, biology.protein, medicine, Cancer research, L-selectin, Neurology (clinical), Biological response modifiers |
| الوصف: | BACKGROUND Up to 60% of melanoma patients develop brain metastases (BrM). These patients have a poor prognosis and limited treatment options. Immune checkpoint inhibitors (ICI) targeting Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and Programmed cell death protein-1 (PD-1) have revolutionized the treatment of melanoma and their efficacy has been also demonstrated in melanoma BrM. Our group previously demonstrated that ICI (combined α-PD-1 and α-CTLA-4) enhances chemokine-dependent infiltration of cytotoxic T lymphocytes (CTLs) into melanoma BrMs in preclinical models, accompanied by upregulated expression of T cell attracting chemokines in tumours. Notably, CTLs infiltrating BrM expressed only some of the chemokine receptors (CRs) interacting with ICI-induced chemokines in BrM, providing a rationale to over-express the “missing” CRs in T cells to enhance their homing to tumours in the context of adoptive T cell therapy (ACT). MATERIALS AND METHODS OT-I cells were isolated from OT-I mice and differentiated ex vivo into effector (TEF) and memory (TCM) CD8+ T cells. Tumour infiltrating lymphocytes (TILs) from B16 tumour-bearing mice treated with ICI were isolated using magnetic beads, activated and expanded ex vivo. Expression of CRs and activation markers in ex vivo cultured T cells were quantified by qPCR and/or flow cytometry. The migration of human blood CD8+ T cells towards chemokines of interest were measured in ex vivo migration assays. RESULTS The same CRs that were missing on BrM-infiltrating CTLs in vivo models were also absent from OT-I TEF (CCR7low/CD44high/CD62Llow) and TCM (CCR7high/CD44low/CD62Lhigh) cells, as well as from TILs expanded ex vivo for use in ACT. Furthermore, we observed no increase in migration of human T cells towards chemokines interacting with the “missing” CRs in comparison to the baseline migration, suggesting that these CRs are also absent from human T cells. CONCLUSION Ex vivo expanded T cells that are used in ACT are missing several CRs that are interacting with chemokines upregulated in BrM. We hypothesise that the use of genetically engineered T cells expressing the “missing” CRs in ACT has the potential to enhance ACT efficacy in combination with ICI. |
| تدمد: | 1523-5866 1522-8517 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::067c5dd6b7dcb2f1b300c3896832d665 https://doi.org/10.1093/neuonc/noab180.089 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....067c5dd6b7dcb2f1b300c3896832d665 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15235866 15228517 |
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