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Characterization and prevention of stunning, a cytotoxic T lymphocyte inactivating program that impairs adoptive T cell therapy against cancer
- Publication Year :
- 2022
-
Abstract
- Adoptive T cell therapy (ACT) is a promising immunotherapeutic approach to fight cancer by utilising cytotoxic T lymphocytes (CTL), which specifically target and eradicate tumour cells. However, one major limitation of this therapy is the ability of tumours to interfere with the CTL through immune escape mechanisms. In a mouse model of B-cell lymphoma and ACT, we investigate the mechanisms underlying this failure. Our laboratory previously found that tumour antigen-specific CTL fail to eradicate lymphoma cells once the tumour burden reaches a certain threshold. In this case a major proportion of the CTL is lost while those remaining lose their effector function, a process we call “stunning”. Our tumour model enables us to investigate the underlying mechanisms of stunning by comparing characteristics of CTL and tumour cells in a small tumour setting, where CTL successfully eradicate tumour cells with a large tumour setting, where stunning occurs. In Chapter 3, we describe findings that suggest that the number of tumour cells presenting a CTL’s specific antigen rather than the total tumour burden determines ACT outcome in our murine lymphoma model. Once the number of antigen+ tumour target cells reaches a critical threshold, all CTL are rendered dysfunctional. We therefore hypothesize that a large heterogenous tumour may be more efficiently killed by using a number of CTL specific for several different antigens simultaneously, where each antigen is only expressed on a subpopulation of tumour cells to prevent CTL dysfunction due to high target cell density. We further showed that increasing numbers of antigen+ tumour cells at the time of adoptive transfer induce the rapid expansion of an Interleukin (IL)-18-receptor-alpha (IL18Ra) and Neuropilin-1 (NRP-1) double positive CTL population, with reduced cytotoxicity. The higher the number of antigen+ tumour cells encountered by the CTL upon transfer, the lower the cytotoxicity, cytokine production and T cell receptor (TCR)
Details
- Database :
- OAIster
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1373008189
- Document Type :
- Electronic Resource