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Title: Cellular and molecular events controlling acquisition of cytotoxic activity by melanoma-reactive CD4+ T cells in vivo
Author: Bergerhoff, K. F.
ISNI:       0000 0004 7428 9740
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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While there is an abundance of studies on cytotoxic CD8+ T cells in cancer immunotherapy, CD4+ T cells with cytotoxic potential are receiving increasing attention from the scientific community. Previously, our lab has underscored the significance of tumour reactive CD4+ T cells which acquire cytotoxic activity during immunotherapy of malignant melanoma. This study aims to analyse and characterise the molecular and cellular mechanisms underlying the function of these cytotoxic CD4+ T cells. On protein and transcript level, cytotoxic tumour infiltrating CD4+Trp1 T cells exhibited a highly plastic phenotype: Th1 and Th2 specific transcription factors Gata3 and T-bet were co-expressed and inflammatory cytokines IFNγ, TNF-α and IL-2 were secreted. Additionally, CD8+ lineage specific transcription factor Runx3 expression was elevated and correlated highly with GzmB expression. However, and in contrast to classical CD8+ CTLs, cytotoxic CD4+Trp1 T cells lacked expression of CD8+ transcription factor Eomes. In depth microarray analysis via Canonical Correspondence Analysis (CCAM) revealed a high correlation of tumour infiltrating CD4+Trp1 cells with a full effector CD8+ T cell gene signature rather than a CD4+ or CD8+ memory phenotype. The strong correspondence with differentiated CD8+ effector T cells prompted the investigation of the role of mTOR signalling in CD4+ cytotoxicity as mTOR activity is crucial for CD8+ effector differentiation. Inhibition of mTORC1 activity by administration of rapamycin and genetic engineering of CD4+Trp1 cells was evaluated. Disruption of mTORC1 signalling counteracted the acquisition and/or maintenance of a cytotoxic phenotype whilst preserving the capacity to produce inflammatory cytokines. This study illustrates the complexity of this highly plastic, cytotoxic CD4+ T cell subset and highlights the importance of mTORC1 signalling for the cytotoxic activity of tumour specific CD4+Trp1 T cells.
Supervisor: Quezada, S. A. ; Peggs, K. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available