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Title: Targeting homeobox genes for cancer immunotherapy
Author: Bokaee, Shadi
ISNI:       0000 0004 2713 0999
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 2011
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Immunotherapy is a complementary or alternative approach to current treatment strategies for cancer. The clinical goal of tumour immunotherapy is to elicit either active or passive immunity directed against tumour antigens by harnessing the immune system to target tumours and thereby break tolerance and improve survival and quality of life of cancer patients. There is a need to identify and target clinically relevant antigens for immunotherapy which could be used to treat a greater proportion of cancer patients. We studied the immunotherapeutic potential of EN2, HOXA1 and HOXB13 (members of the HOX family) as vaccine targets in this project. Homeodomain-containing proteins (HOX) are transcription factors that regulate the co-ordinated expression of multiple genes involved in development, differentiation and malignant transformation. Immunohistochemical studies on high-density melanoma, breast and ovarian cancer tissue arrays (to assess EN2, HOXA1 and HOXB13 expression respectively) showed a large proportion of cancer cores over-expressing these antigens compared to normal tissues. Moreover, the autoantibody response to these antigens was examined in cancer patients using ELISA assays. Further to this, we used a reverse immunology strategy to identify several immunogenic HLA-A2 restricted EN2, HOXA1 and HOXB13 epitopes which were observed to generate peptide specific immune responses in the majority of donors tested. This was done by repeated peptide stimulation of PBMC from healthy donors and screening against T2 cells loaded with or without the relevant peptide in IFN-y ELISPOT assays. Alongside this, HOXA1-specific T cells were tested against breast cancer cell lines, suggesting these epitopes are naturally processed and presented. Our findings suggest EN2 and HOXA1 as potential promising targets for vaccine therapy to treat melanoma and breast cancer patients respectively. Although peptide-based cancer vaccines are capable of eliciting measurable immune responses in various types of cancer, objective clinical responses remain infrequent and transient. One explanation for this tumour escape is immunosuppression mediated by a subset of T cells known as T regulatory cells (Treg) that can block effective anti-tumour immune responses. We have developed a peptide (HWFT) that blocks the interaction between the Treg specific transcription factor, FOXP3 and its co-factor NFAT. Upon treatment of sorted murine splenocyte populations with HWFT we showed specific apoptosis of Tregs compared to non-Tregs as assessed by annexinV/7AAD FACS analysis. Furthermore, it was observed that HWFT inhibits murine Treg suppressive function in proliferation assays as well as inhibiting the production of the IL-10 suppressive cytokine. However, in humans, HWFT inhibits Treg suppressive capacity without killing. In addition, we assessed the effects of HWFT on immune responses against common recall antigens in in vitro assays using the PBMC of healthy individuals and cancer patients. This was compared with anti CD25 depletion as an alternative Treg targeting method. The results showed enhanced immune responses against common recall antigens upon HWFT treatment in cancer patients. In both systems non-Treg cells are spared, suggesting that our peptide represents a more specific and potentially less toxic method for targeting Tregs to relieve immune suppression than any other current treatment. Consequently, we believe the pre-clinical development of our peptide will lead to a safer and more effective modulation of Treg across a range of different cancers as a combination therapy with vaccines or other treatment modalities.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available