Ferry, Gabrielle Margaret; (2022) Expanding and Developing Vδ1 T Lymphocytes as a Cancer Immunotherapeutic. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Adoptive cell transfer (ACT) involving either genetically modified or unmanipulated cells is one of the leading forms of cancer immunotherapy currently in development. While ACT has proven successful in several haematological malignancies, its limited efficacy in the context of solid tumours demands further innovation within this field. Vδ1 cells are unconventional T lymphocytes that possess innate tissue-resident properties that could confer prolonged persistence within solid tumours. Unlike canonical αβT cells, these cells function independently of MHC-antigen presentation, instead relying on mechanisms that protect healthy, non-transformed cells. Vδ1 cells are also resistant to activation-induced cell death and can be found in tumour infiltrates, indicating their potential for long-term survival and function. Thus, Vδ1 cells present an allogeneic therapeutic platform that can exhibit prolonged effector function and signalling to promote antitumour immunity within a solid tumour context. Unfortunately, Vδ1 cells comprise a low frequency of circulating adult T cells and exhibit limited, if any, expansion ex vivo in the presence of other more proliferative immune cells. One important study in recent years demonstrated successful expansion of therapeutically relevant Vδ1 cells using a milieu of inflammatory cytokines. Using a modified version of their described protocol, we examined in vitro expansion and function of Vδ1 cells from adult peripheral blood using only the essential cytokine IL-15. However, we found that once expanded with IL-15, Vδ1 cells dependent on its supplementation for continued survival and function. Although we investigated two methods of obviating this cytokine dependence, we sought to identify an alternative means to overcoming the need for IL-15. Thus, we also explored expansion from umbilical cord blood, as foetal Vδ1 cells were thought to manifest naïve-like characteristics and to be primed for robust proliferation. Here, we discovered an unexpected role of IL-15 in cord blood Vδ1 phenotypic marker expression and maintenance.

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