T CELL HOMEOSTASIS · Conditioning regimens shape the homeostasis of adoptively transferred T cells: Effects on autoreactivity and role in anti-tumor therapy
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2010-01-01 → 2013-12-31
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-IRG
Линиите свързват координатора с партньорите.
Накратко на български
Различните методи за подготвяне на организма (например облъчване или химиотерапия) влияят върху това как се развиват пренесените Т-клетки при борбата с тумори. Това помага да се разбере как да се подобри ефективността и устойчивостта на имунотерапията при рак.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Conditioning regimens shape the homeostasis of adoptively transferred T cells: Effects on autoreactivity and role in anti-tumor therapy
Executive Summary: Many advances in cancer therapy have been achieved during the past decade but metastatic cancers remain extremely difficult to treat. As a result, new strategies are being developed with one focus aimed at harnessing the immune system to target and eradicate tumors. Adoptive T cell immunotherapy involves the transfer of tumor-specific T cells that have been manipulated and expanded ex vivo. While immunotherapy strategies have demonstrated their potential, optimizing the persistence and responsiveness of adoptively transferred T cells remains a significant challenge. As lymphopenia itself results in the differentiation and activation of the T cell compartment, the induction of this state has been exploited to enhance the anti-tumor efficacy of adoptively transferred T cells. However, we have only little knowledge as to whether different lymphopenia-inducing regimens are equal in their capacity to “support” T cell expansion and differentiation to T effector fates. Here, we show that the fate of T cell populations is strikingly changed by adoptive transfer into mice rendered lymphopenic by sub-lethal irradiation as compared to a busulphan/cyclophosphamide (Bu/Cy) chemotherapy regimen. Irradiation-mediated lymphopenia resulted in a skewed proliferation of donor CD8+ T cells whereas Bu/Cy treatment induced a massive IL-7-independent proliferation of donor CD4+ T cells. Notably, this latter proliferation was associated with a significant expansion of adoptively transferred Foxp3+ suppressive T cells in Bu/Cy-treated mice. As the level of lymphopenia induced by chemotherapy and irradiation was very similar, our data strongly suggest that conditioning-triggered changes in the host environment, rather than lymphopenia per se, modulate the fate of adoptively transferred T cells. Indeed, our data show that the numbers as well as subsets of dendritic cells (DCs) differ in irradiated and Bu/Cy-treated mice. Furthermore, we observed a very different spatial organization of the lymphoid tissues in the 2 different lymphopenic environments and important variations in cytokine availability. Moreover, efficient depletion of host DC significantly attenuated the fast proliferation of adoptively-transferred CD4+ T cells in Bu/Cy-treated mice. Thus, lymphopenia-inducing regimens are not equivalent and our data demonstrate that their distinct effects on host DC subsets regulate the proliferation and function of adoptively-transferred T cells. An understanding of these parameters will be crucial for the future development of immunotherapy protocols.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
The ability of adoptively-transferred T cells to mediate an immune response is modulated by the host environment. It has previously been shown that donor T cells proliferate and acquire memory-like characteristics when injected into lymphopenic hosts while in hosts with a « full » T cell compartment, they remain naïve and do not acquire effector function. As it is important to optimize the persistence and responsiveness of transferred T cells for immunotherapy strategies, we assessed whether T cell fate is dependent upon the conditioning regimen used to achieve lymphopenia. We induced lymphopenia in C57Bl/6 mice by sub-lethal irradiation or chemotherapy using busulfan with cyclophosphamide (Bu/Cy) and found that the relative engraftment of CD4 and CD8 T cells was markedly changed by the conditioning protocol: Irradiation-induced lymphopenia resulted in a skewed proliferation of donor CD8 T cells with a CD4:CD8 ratio of <1:5 whereas Bu/Cy-induced lymphopenia resulted in a massive proliferation of donor CD4 T cells with only minimal proliferation of CD8 T cells. These results clearly demonstrate that lymphopenic conditions are not equivalent in their potential to foster the regeneration of T cell pools. I propose to study the characteristics of the host and adoptively-transferred T cells generated in these two lymphopenic environments, with specific assessment of TH1, TH17 and Treg subsets. As the host microenvironment modulates T cell persistence and function, the effects of these regimens on the fate of stromal cell and APC populations will also be monitored. Moreover, I will study the consequences of irradiation and Bu/Cy conditioning on the reconstitution and function of adoptively-transferred T cells harboring a re-directed tumor-specific TCR in mice harbouring B cell lymphomas. The identification of parameters that enhance the survival and reactivity of adoptively-transferred tumor-specific T cells is important for the development of immunotherapy strategies
Оригинален текст от CORDIS (на английски).
Участници
- CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS · ParisКоординаторФранция
Връзки
Данни: CORDIS, © Европейски съюз