Microbiology & Immunology - Theses
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ItemInactivation Mechanisms of Therapeutic CD8+ T Cells against a non-Hodgkin B-cell Lymphoma Mouse Model( 2021)Clinical and animal studies have demonstrated the capability of innate or adaptive components of the immune system to eliminate tumour cells. Cytotoxic CD8 T lymphocytes (CTLs) are the main population of the adaptive immune system involved in tumour cells elimination. In clinical studies, autologous tumour associated antigen (TAA)-specific CTLs have been adoptively transferred into patients to eliminate tumour cells expressing the cognate antigen, an approach known as Adoptive Cell Therapy (ACT). In many conditions, these CTLs are functionally impaired. Similar observations have been made in mouse models, including our own. We found that anti-ovalbumin (OVA) OT-I CTL injected into mice were capable of eliminating non-Hodgkin B cell lymphoma cells that express OVA as a model TAA. However, this ACT failed in mice harbouring a large tumour burden because many of the OT-I CTL were eliminated soon after ACT, and even though the surviving ones expanded, they remained functionally impaired. These observations recapitulate successful vs failed outcomes of ACT in the clinic. So far little is known about the extrinsic and intrinsic mechanisms that determine these outcomes. My results show that the mechanisms of CTL inactivation we observe are most likely physiological responses to large target cell burdens and provide experimental system to further understand the mechanisms of inactivation and approaches for the generation of more effective CTL for ACT.