부산대학교 도서관

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.