T CELL HOMEOSTASIS

Conditioning regimens shape the homeostasis of adoptively transferred T cells: Effects on autoreactivity and role in anti-tumor therapy

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 Obiettivo del progetto (Objective)

'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'

Introduzione (Teaser)

Metastatic cancers are extremely difficult to treat and scientists are working on harnessing the immune system to target tumours. A technique called adoptive T cell immunotherapy (ATCI)can induce cancer regression in early-stage clinical trials.

Descrizione progetto (Article)

ATCI involves the transfusion of the patient's T cells (part of the immune system) after ex vivo manipulation to eliminate tumours and prevent its recurrence. Though ATCI shows promise, this treatment could be optimised by improving the persistence and responsiveness of transferred T cells.

Lymphopenia (LP) is characterised by abnormally low levels of lymphocytes in the blood that is seen after chemotherapy or medical whole body radiation. LP can stimulate the differentiation and activation of the T cell compartment and this can be exploited to improve the efficacy of ATCI treatment.

The EU funded T CELL HOMEOSTASIS project focused on identifying parameters that enhance the survival and reactivity of adoptively-transferred tumour-specific T cells.

Researchers established that irradiation-mediated LP skewed the proliferation of donor T cells, whereas chemotherapy induced a massive proliferation of donor T cells. These data strongly suggested that conditioning triggered changes in the host environment, rather than LP modulating the fate of adoptively transferred T cells. Indeed, further studies showed that the numbers as well as subsets of other types of immune cells differ in irradiated and chemo-treated mice. Furthermore, a very different spatial organisation of the lymphoid tissues was observed in these different LP environments.

T CELL HOMEOSTASIS demonstrated that LP-inducing regimens are not equal and that their distinct effects on immune cell subsets regulate adoptively-transferred T cells. An understanding of these parameters will be crucial for the future development of immunotherapy protocols.