The complement C5a receptor facilitates cancer metastasis by altering T cell responses in metastases-targeted organs (TUM2P.883)
| Autor: | Sharad Sharma, Navinkumar Chitala, Suryakumari Vadrevu, Priya Sharma, Clayton Cleveland, Linley Riediger, David Fairlie, Wojciech Gorczyca, Othon Almanza, Magdalena Karbowniczek, Maciej Markiewski |
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| Rok vydání: | 2014 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 192:71.7-71.7 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.192.supp.71.7 |
| Popis: | The role of complement in cancer metastasis has not yet been recognized. In addition, involvement of adaptive immunity in preventing metastasis to the vital organs is unclear. Here we show that the complement anaphylatoxin C5a receptor (C5aR) facilitates metastasis by suppressing effector CD8+ and CD4+ T cell responses in the lungs. Mechanisms of this suppression involve recruitment of immature myeloid cells co-expressing TGF-β and IL-10 to this organ. TGF- β and IL-10 favored generation of inducible T regulatory (iTreg) cells and Th2 responses that rendered CD8+ T cells dysfunctional. Importantly, pharmacological blockade of C5aR or its genetic ablation in C5aR-deficient mice prevented metastases in a syngeneic model of breast cancer. CD8+ T cell depletion abolished beneficial effect of C5aR blockade on metastasis suggesting that presence of CD8+ T cells is required for C5aR blockade-mediated protection from metastasis. These data reveal a surprising and contrasting role of C5aR-signaling in cancer metastasis that enables iTreg cell generation and suppress T cell responses. Furthermore, present study opens a new avenue for developing complement-based immunotherapies to prevent or reduce cancer metastasis. |
| Databáze: | OpenAIRE |
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