The Ovarian Cancer Tumour Microenvironment Modulates Natural Killer Cell Function

Abstract

Natural killer (NK) cells mediate anti-tumour responses but are inhibited in the high-grade serous carcinoma (HGSC) microenvironment by factors including adenosine (ado) and human leukocyte antigen (HLA)-E/natural killer group 2A (NKG2A) checkpoint. Using flow cytometry, I assessed how ado alters HGSC cells and NK phenotypes. I genotyped HGSC patients for NKG2A polymorphisms and tested their impact on patient outcomes and immune profiles, and I genotyped healthy donors to assess NKG2A polymorphism impact on NK function in vitro. CD16 expression defined two NK subsets with distinct responses to ado; only CD16low NK cells were suppressed by ado-treated targets. NKG2A variant 5 (V5) associated with higher NKG2A expression and stronger responses to HLA-Elow targets. Ado enhanced HLA-E/NKG2A expression and NKG2A polymorphisms dictated ado suppression, revealing a novel link between metabolic and checkpoint inhibition. These findings support dual targeting of ado metabolism and NKG2A to overcome NK suppression in the HGSC microenvironment.