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