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Molecular and cellular basis of T-cell responses to melanoma antigens

Bianchi, Valentina 2016. Molecular and cellular basis of T-cell responses to melanoma antigens. PhD Thesis, Cardiff Univeristy.
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Abstract

Background ⎯ Malignant melanoma is an aggressive form of skin cancer with poor prognosis. Current immunotherapies targeting melanoma using the patient’s immune system can achieve long-­‐term melanoma clearance in some patients. T-­‐cells are the main effectors of this anti-­‐melanoma immunity and can specifically recognise and lyse tumour cells. T-­‐cells express unique surface T-­‐cell receptors (TCR) which recognise tumour-­‐derived peptide antigens bound to a Human Leukocyte Antigen (HLA) molecule on melanoma cells. My research aimed at studying anti-­‐melanoma T-­‐cell responses from both a molecular and cellular level. Results ⎯ Initially, I analysed the first crystallographic structure of a TCR in complex with a peptide from the melanoma protein Glycoprotein(gp)100 bound to HLA-­‐A2. I show that an unanticipated molecular switch of the position(P)4-­‐5 peptide bond by substitution of the 3 residue could brogate recognition by host TCRs. I then dissected successful T-­‐cell responses, restricted to specific HLA alleles, in melanoma infiltrates from two complete responder (CR) patients after Tumour Infiltrating Lymphocyte (TIL) therapy. The antigen specificity and phenotype of anti-­‐melanoma TILs were evaluated, and a panel of TIL clones capable of lysing autologous melanoma cell targets was characterised. Interestingly, in each patient studied, melanoma-­‐specific clonotypes detected Background⎯ Malignant melanoma is an aggressive form of skin cancer with poor prognosis. Current immunotherapies targeting melanoma using the patient’s immune system can achieve long-­‐term melanoma clearance in some patients. T-­‐cells are the main effectors of this anti-­‐melanoma immunity and can specifically recognise and lyse tumour cells. T-­‐cells express unique surface T-­‐cell receptors (TCR) which recognise tumour-­‐derived peptide antigens bound to a Human Leukocyte Antigen (HLA) molecule on melanoma cells. My research aimed at studying anti-­‐melanoma T-­‐cell responses from both a molecular and cellular level. Results ⎯ Initially, I analysed the first crystallographic structure of a TCR in complex with a peptide from the melanoma protein Glycoprotein(gp)100 bound to HLA-­‐A2. I show that an unanticipated molecular switch of the position(P)4-­‐5 peptide bond by substitution of the P3 residue could abrogate recognition by host TCRs. I then dissected successful T-­‐cell responses, restricted to specific HLA alleles, in melanomainfiltrates from two complete responder (CR) patients after Tumour Infiltrating Lymphocyte (TIL) therapy. The antigen specificity and phenotype of anti-­‐melanoma TILs were evaluated, and a panel of TIL clones capable of lysing autologous melanoma cell targets was characterised. Interestingly, in each patient studied, melanoma-­‐specific clonotypes detected in the TILs persist in the blood after TIL therapy and recognise T-­‐cell epitopes shared by other patients and other tumour types. Conclusions ⎯ I demonstrate that structural studies should be considered when designing improved peptide cancer vaccines as even single substitutions in residues not heavily engaged by the TCR can have important, unpredictable knock-­‐on effects that impair T-­‐cell recognition. Understanding the key antigen-­‐specificities of anti-­‐tumour TILs from CR patients, will improve the efficacy of T-­‐cell based therapies. Validated antigens could be applied as biomarkers of, or targets for, cancer immunotherapy. Dominant shared antigens targeted in CR patients may make promising candidates for therapeutic vaccination.

Item Type: Thesis (PhD)
Date Type: Publication
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Date of First Compliant Deposit: 14 July 2016
Last Modified: 17 Mar 2017 05:52
URI: http://orca-mwe.cf.ac.uk/id/eprint/92547

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