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approved checkpoint therapy indicated for metastatic melanoma 37,38 . CTLA-4 was followed
                by PD-1 and eventually PD-L1 blockade therapy 39-41 . The unprecedented clinical impact of
                immune checkpoint blockade therapy induced a new era of cancer treatment , resulting in
                additional targets like TIM-3  and TIGIT . The addition of targetable immune mechanisms is
                necessary, as many patients that initially responded to immunotherapy relapse and progress
                after a period of time, a clinical scenario called acquired resistance , indicating the need for
                follow up or combination therapies.

                ACQUIRED RESISTANCE BY HLA-E/Qa-1   b

                One  of  the  novel  immune  checkpoint  targets  is  NKG2A,  which  is  expressed  by  natural
                killer cells, NKT cells and activated CD8 T cells. NKG2A forms a heterodimer with CD94 and
                engages HLA-E, a non-classical MHC class I protein. HLA-E is ubiquitously expressed, but at
                low levels and very high expressions can only be found on trophoblasts and ductal epithelial
                cells in immune-privileged tissues like placenta and testis, respectively. In cancers, HLA-E
                is  frequently  overexpressed  compared  to  their  non-transformed  counterparts,  including
                melanoma and carcinomas of lung, cervix, ovarium, vulva, and head/neck 45-50 . This thesis is
                focused on the NKG2A – HLA-E axis and its targeting for immunotherapy of cancer.

                SCOPE OF THIS THESIS

                The NKG2A - HLA-E axis has been shown to induce inhibition on cytotoxic NK and CD8 T
                cells. The HLA-E homolog in the mouse is named Qa-1 . In this thesis, we reviewed the
                literature on both the ligand HLA-E/Qa-1  and its receptor NKG2A in the context of cancer
                immunity in Chapter 2. In Chapter 3, we studied the expression of NKG2A in relation to
                other well-known inhibitory receptors involved in cancer therapy. We show that NKG2A on
                activated CD8 T cells, similar to TIM3 and in contrast to PD-1, is a late inhibitory receptor
                and is induced following repeated rounds of stimulation. We also show that the expression
                of NKG2A is related to dividing T cells, that its expression is affected by TGF-β and that
                NKG2A expressing CD8 T cells express genes associated tissue residency and a cytolytic
                phenotype.  In  Chapter  4,  we  focused  on  the  expression  of  NKG2A  and  HLA-E/Qa-1   in
                tumor mouse models in combination with an immune active tumor environment induced
                by cancer vaccines. We show that by interrupting the axis via NKG2A blocking antibodies or
                genetic Qa-1  knock down in tumor cell lines, the potency of cancer vaccines is improved,
                resulting in stronger tumor regressions, longer progression free survival and more cures. In
                Chapter 5, we evaluated the role of Qa-1  on tumor infiltrate. Absence of Qa-1  on tumor
                cells resulted in an increased frequency of CD8 T cells and better response to vaccination.
                Qa-1  expression on other cell than the tumor did not affect therapy response. We also
                examined the role for Qa-1  in other tumor therapies. For chemotherapy with cisplatin Qa-
                1  had a subtle negative effect. The impact of radiotherapy on tumor outgrowth seemed
                to depend on Qa-1  expression by the tumor. Finally, in Chapter 6, we discuss the overall
                results obtained during this research adventure and place these findings in the broader
                context of T-cell based immunotherapy of cancer. Taken together, the findings described in
                this thesis provide new insights into the expression profile of NKG2A, blocking the axis of
                NKG2A and HLA-E/Qa-1  and how this affects cancer treatments.
                12                                                                CHAPTER 1
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