Page 14 - linda_borst
P. 14

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
                                                                               42
                additional targets like TIM-3  and TIGIT . The addition of targetable immune mechanisms is
                                       43
                                                44
                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
                                                                      6
                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
                                                              b
                literature on both the ligand HLA-E/Qa-1  and its receptor NKG2A in the context of cancer
                                                  b
                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
                                                                                       b
                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,
                           b
                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
                                                  b
                                                                                 b
                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
                    b
                examined the role for Qa-1  in other tumor therapies. For chemotherapy with cisplatin Qa-
                                      b
                1  had a subtle negative effect. The impact of radiotherapy on tumor outgrowth seemed
                 b
                to depend on Qa-1  expression by the tumor. Finally, in Chapter 6, we discuss the overall
                                b
                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.
                                    b
                12                                                                CHAPTER 1
   9   10   11   12   13   14   15   16   17   18   19