Cancer-associated fibroblasts drive CXCL13 production in activated T cells via TGF-beta
IntroductionTumour-reactive T cells producing the B-cell attractant chemokine CXCL13, in solid tumours, promote development of tertiary lymphoid structures (TLS) and are associated with improved prognosis and responsiveness to checkpoint immunotherapy. Cancer associated fibroblasts are the dominant...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1221532/full |
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| author | Richard A. O’Connor Begoña Roman Martinez Lilian Koppensteiner Layla Mathieson Ahsan R. Akram Ahsan R. Akram |
| author_facet | Richard A. O’Connor Begoña Roman Martinez Lilian Koppensteiner Layla Mathieson Ahsan R. Akram Ahsan R. Akram |
| author_sort | Richard A. O’Connor |
| collection | DOAJ |
| description | IntroductionTumour-reactive T cells producing the B-cell attractant chemokine CXCL13, in solid tumours, promote development of tertiary lymphoid structures (TLS) and are associated with improved prognosis and responsiveness to checkpoint immunotherapy. Cancer associated fibroblasts are the dominant stromal cell type in non-small cell lung cancer (NSCLC) where they co-localise with T cells and can influence T cell activation and exhaustion. We questioned whether CAF directly promote CXCL13-production during T cell activation.MethodsWe characterised surface markers, cytokine production and transcription factor expression in CXCL13-producing T cells in NSCLC tumours and paired non-cancerous lung samples using flow cytometry. We then assessed the influence of human NSCLC-derived primary CAF lines on T cells from healthy donors and NSCLC patients during activation in vitro measuring CXCL13 production and expression of cell-surface markers and transcription factors by flow cytometry.ResultsCAFs significantly increased the production of CXCL13 by both CD4+ and CD8+ T cells. CAF-induced CXCL13-producing cells lacked expression of CXCR5 and BCL6 and displayed a T peripheral helper cell phenotype. Furthermore, we demonstrate CXCL13 production by T cells is induced by TGF-β and limited by IL-2. CAF provide TGF-β during T cell activation and reduce availability of IL-2 both directly (by reducing the capacity for IL-2 production) and indirectly, by expanding a population of activated Treg. Inhibition of TGF-β signalling prevented both CAF-driven upregulation of CXCL13 and Treg expansion.DiscussionPromoting CXCL13 production represents a newly described immune-regulatory function of CAF with the potential to shape the immune infiltrate of the tumour microenvironment both by altering the effector-function of tumour infiltrating T-cells and their capacity to attract B cells and promote TLS formation. |
| first_indexed | 2024-03-12T23:51:04Z |
| format | Article |
| id | doaj.art-37468c95f769494c955544501692f05b |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-12T23:51:04Z |
| publishDate | 2023-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-37468c95f769494c955544501692f05b2023-07-13T13:39:17ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-07-011410.3389/fimmu.2023.12215321221532Cancer-associated fibroblasts drive CXCL13 production in activated T cells via TGF-betaRichard A. O’Connor0Begoña Roman Martinez1Lilian Koppensteiner2Layla Mathieson3Ahsan R. Akram4Ahsan R. Akram5Centre for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, United KingdomCentre for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, United KingdomCentre for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, United KingdomCentre for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, United KingdomCentre for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, United KingdomCancer Research UK Scotland Centre, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, United KingdomIntroductionTumour-reactive T cells producing the B-cell attractant chemokine CXCL13, in solid tumours, promote development of tertiary lymphoid structures (TLS) and are associated with improved prognosis and responsiveness to checkpoint immunotherapy. Cancer associated fibroblasts are the dominant stromal cell type in non-small cell lung cancer (NSCLC) where they co-localise with T cells and can influence T cell activation and exhaustion. We questioned whether CAF directly promote CXCL13-production during T cell activation.MethodsWe characterised surface markers, cytokine production and transcription factor expression in CXCL13-producing T cells in NSCLC tumours and paired non-cancerous lung samples using flow cytometry. We then assessed the influence of human NSCLC-derived primary CAF lines on T cells from healthy donors and NSCLC patients during activation in vitro measuring CXCL13 production and expression of cell-surface markers and transcription factors by flow cytometry.ResultsCAFs significantly increased the production of CXCL13 by both CD4+ and CD8+ T cells. CAF-induced CXCL13-producing cells lacked expression of CXCR5 and BCL6 and displayed a T peripheral helper cell phenotype. Furthermore, we demonstrate CXCL13 production by T cells is induced by TGF-β and limited by IL-2. CAF provide TGF-β during T cell activation and reduce availability of IL-2 both directly (by reducing the capacity for IL-2 production) and indirectly, by expanding a population of activated Treg. Inhibition of TGF-β signalling prevented both CAF-driven upregulation of CXCL13 and Treg expansion.DiscussionPromoting CXCL13 production represents a newly described immune-regulatory function of CAF with the potential to shape the immune infiltrate of the tumour microenvironment both by altering the effector-function of tumour infiltrating T-cells and their capacity to attract B cells and promote TLS formation.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1221532/fullcancer associated fibroblastT cellCXCL13Tregnon-small cell lung cancer |
| spellingShingle | Richard A. O’Connor Begoña Roman Martinez Lilian Koppensteiner Layla Mathieson Ahsan R. Akram Ahsan R. Akram Cancer-associated fibroblasts drive CXCL13 production in activated T cells via TGF-beta Frontiers in Immunology cancer associated fibroblast T cell CXCL13 Treg non-small cell lung cancer |
| title | Cancer-associated fibroblasts drive CXCL13 production in activated T cells via TGF-beta |
| title_full | Cancer-associated fibroblasts drive CXCL13 production in activated T cells via TGF-beta |
| title_fullStr | Cancer-associated fibroblasts drive CXCL13 production in activated T cells via TGF-beta |
| title_full_unstemmed | Cancer-associated fibroblasts drive CXCL13 production in activated T cells via TGF-beta |
| title_short | Cancer-associated fibroblasts drive CXCL13 production in activated T cells via TGF-beta |
| title_sort | cancer associated fibroblasts drive cxcl13 production in activated t cells via tgf beta |
| topic | cancer associated fibroblast T cell CXCL13 Treg non-small cell lung cancer |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1221532/full |
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