T9CAN · Transcriptional regulation of IL-9-producing CD4 T cells: use in cancer immunotherapy
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2012-04-01 → 2016-03-31
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-CIG
Линиите свързват координатора с партньорите.
Накратко на български
Т-хелперни клетки от тип 9 (Th9) и механизмите, чрез които протеинът IL-1beta ги активира за борба с туморите, са в центъра на анализа. Разбирането на тези процеси помага за подобряване на имунотерапията при рак.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Transcriptional regulation of IL-9-producing CD4 T cells: use in cancer immunotherapy
This proposal aims to unravel the molecular bases accounting for the anticancer properties of IL-1beta-induced IL-9-producing CD4 T cells (Th9 cells). Th9 cells have been characterized in 2008 as a proinflammatory CD4 T cell subset. While these cells were originally shown to promote inflammation in colitis and asthma, recent work now suggests that these cells also harbor potent anticancer properties. However, the mechanisms leading to the generation of these cells remain incompletely understood. Similarly, the potential contribution of other immune effector cells to the anticancer activity of Th9 cells is elusive. Thus, despite their anticancer properties, the limited knowledge on the ways to control Th9 cell effector functions restricts their putative use for cancer immunotherapy. Our preliminary data indicated that Th9 cells feature superior anticancer properties when induced in the presence of the proinflammatory factor interleukin-1beta (IL-1beta) relatively to Th9 cells obtained in conventional conditions. This striking activity suggested that such Th9 cells play a dominant role in the control of tumor growth. We found that IL-1# does not merely enhance the generation of Th9 cells but selectively induces the expression of the transcription factor IRF1 in developing Th9 cells that dictates their effector functions and anticancer properties. We will have deciphered the molecular series of transcriptional events that ultimately confer anticancer properties to IL-1beta-induced Th9 cells. Specifically, we have identified that the activation of the IL-1R>MyD88>Stat1>Irf1 pathway enhances Th9 cell functions and anticancer activity. Finally, we found that the anticancer efficacy of Th9 cells induced in the presence of IL-1beta depends on IL-21 and on the activation of immune effector NK and CD8 T cells in vivo. These findings provide a mean to modulate the biological activity of Th9 cells to contemplate their use in cancer immunotherapy.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Differentiation of naïve CD4 T cells in presence of TGF-beta and IL-4 has led to the identification of a novel IL-9-secreting-population of CD4 T cells, Th9 cells, which are characterized by their potent IL-9 release and their ability to induce proinflammatory responses in vivo. Co-transfer of in vitro differentiated Th9 cells from naïve T cells along with effector cells increase the severity of colitis in mice. Proinflammatory functions of Th9 cells have also been documented in the mouse model of human multiple sclerosis, Experimental Autoimmune Encephalomyelitis (EAE), in asthma and the existence of Th9 cells has been confirmed in humans. Nevertheless, while the transcription factors PU.1 and irf4 have been involved in Th9 cell development in mouse and humans, the mechanisms leading to the generation of these cells remain incompletely understood. In addition, the function of Th9 cells in cancer has never been explored. Our preliminary work suggests that the addition of a proinflammatory factor IL-1 beta during Th9 cell differentiation triggers the high expression of a transcription factor, which might cooperate with irf4 and PU.1 to dramatically enhance Th9 cell effector functions. Generation of Th9 cells in the presence of IL-1 beta also enhances the antitumor properties of Th9 cells in vivo. In this project, we aim to decipher the molecular mechanisms responsible for the effect of IL-1 beta on Th9 cells and identify the factors responsible for the anticancer efficacy of Th9 cells in vivo. Unraveling the mechanisms responsible for the enhanced anticancer efficacy of Th9 cells would not only provide a better characterization of Th9 cell development but would also urge scientists to contemplate their use in cancer immunotherapy.
Оригинален текст от CORDIS (на английски).
Участници
- INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisКоординаторФранция
Връзки
Данни: CORDIS, © Европейски съюз