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The role of T cells in cutaneous squamous cell carcinoma

The role of T cells in cutaneous squamous cell carcinoma
The role of T cells in cutaneous squamous cell carcinoma
Cutaneous squamous cell carcinoma (cSCC) is the most common form of human cancer with metastatic potential. Despite T cells accumulating around cSCCs, these tumours continue to grow and persist. To investigate reasons for the failure of T cells to mount a protective response in cSCC, tumoral T cells were characterised to determine factors responsible for cSCC T cell dysfunction. This thesis focused primarily on regulatory T cells (Tregs, which are considered immunosuppressive) and CD8+ T cells (thought to be responsible for destroying cancer cells) within the population of T cells surrounding cSCCs.

Human primary cSCCs contained increased FOXP3+ Treg and CD8+ T cell frequencies compared with corresponding peripheral blood and normal skin. Most tumoral T cells expressed the skin addressin CLA and E-selectin was detected in the majority of peritumoral blood vessels. Functional studies showed that tumoral Tregs suppressed tumoral effector CD4+ and CD8+T cell proliferation and effector T cell interferon-γ secretion in vitro. OX40 was expressed by higher proportions of tumoral Tregs than other T cells (including CD4+FOXP3- and CD8+ T cells) and increased OX40+ lymphocyte frequencies were observed in primary cSCCs which metastasised compared with primary cSCCs which had not metastasised. Furthermore, in vitro OX40 activation of Treg/CD4+ effector T cell co-cultures enhanced tumoral CD4+ T cell proliferation, thus overcoming Treg suppression.

Functional data demonstrated that CD8+ T cells from cSCC were less able to proliferate and produce granzyme B and perforin in vitro than CD8+ T cells from peripheral blood. In addition, IL-2 was produced by fewer T cells in cSCC than in normal skin. The inhibitory receptor PD-1 was expressed by higher proportions of T cells in cSCC than peripheral blood and PD-1 inhibition augmented in vitro tumoral CD8+ T cell proliferation.

The results in this thesis highlight that dysfunctional T cell responses are present in cSCC, potentially contributing to ineffective anti-tumour immunity and permitting the development and growth of cSCC. Furthermore, the data in this thesis show that T cells from cSCC can be used for functional assessment of T cell costimulatory/inhibitory antibodies, suggesting this system might be useful as a preclinical tool for investigation of anti-tumour immunotherapies.
University of Southampton
Lai, Chester
8f0277cf-7bb9-4883-8b73-a6cd755df7dd
Lai, Chester
8f0277cf-7bb9-4883-8b73-a6cd755df7dd
Healy, Eugene
400fc04d-f81a-474a-ae25-7ff894be0ebd
Al-Shamkhani, Aymen
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Lai, Chester (2016) The role of T cells in cutaneous squamous cell carcinoma. University of Southampton, Doctoral Thesis, 274pp.

Record type: Thesis (Doctoral)

Abstract

Cutaneous squamous cell carcinoma (cSCC) is the most common form of human cancer with metastatic potential. Despite T cells accumulating around cSCCs, these tumours continue to grow and persist. To investigate reasons for the failure of T cells to mount a protective response in cSCC, tumoral T cells were characterised to determine factors responsible for cSCC T cell dysfunction. This thesis focused primarily on regulatory T cells (Tregs, which are considered immunosuppressive) and CD8+ T cells (thought to be responsible for destroying cancer cells) within the population of T cells surrounding cSCCs.

Human primary cSCCs contained increased FOXP3+ Treg and CD8+ T cell frequencies compared with corresponding peripheral blood and normal skin. Most tumoral T cells expressed the skin addressin CLA and E-selectin was detected in the majority of peritumoral blood vessels. Functional studies showed that tumoral Tregs suppressed tumoral effector CD4+ and CD8+T cell proliferation and effector T cell interferon-γ secretion in vitro. OX40 was expressed by higher proportions of tumoral Tregs than other T cells (including CD4+FOXP3- and CD8+ T cells) and increased OX40+ lymphocyte frequencies were observed in primary cSCCs which metastasised compared with primary cSCCs which had not metastasised. Furthermore, in vitro OX40 activation of Treg/CD4+ effector T cell co-cultures enhanced tumoral CD4+ T cell proliferation, thus overcoming Treg suppression.

Functional data demonstrated that CD8+ T cells from cSCC were less able to proliferate and produce granzyme B and perforin in vitro than CD8+ T cells from peripheral blood. In addition, IL-2 was produced by fewer T cells in cSCC than in normal skin. The inhibitory receptor PD-1 was expressed by higher proportions of T cells in cSCC than peripheral blood and PD-1 inhibition augmented in vitro tumoral CD8+ T cell proliferation.

The results in this thesis highlight that dysfunctional T cell responses are present in cSCC, potentially contributing to ineffective anti-tumour immunity and permitting the development and growth of cSCC. Furthermore, the data in this thesis show that T cells from cSCC can be used for functional assessment of T cell costimulatory/inhibitory antibodies, suggesting this system might be useful as a preclinical tool for investigation of anti-tumour immunotherapies.

Text
Chester thesis amended - Version of Record
Restricted to Repository staff only until 20 March 2020.
Available under License University of Southampton Thesis Licence.

More information

Published date: October 2016

Identifiers

Local EPrints ID: 434986
URI: https://eprints.soton.ac.uk/id/eprint/434986
PURE UUID: 6cf36d4d-ee42-479b-9b0a-b1509f3563c7
ORCID for Aymen Al-Shamkhani: ORCID iD orcid.org/0000-0003-0727-4189

Catalogue record

Date deposited: 17 Oct 2019 16:30
Last modified: 18 Oct 2019 00:37

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