Jeanette E Boudreau

Adenosine drives suppression of CD16low NK cell responses against HGSC via NKG2A:hLA-E interactions

Abstract High-grade serous carcinoma (HGSC) of the ovary remains the deadliest gynecologic cancer, with 5-year survival rates of less than 50%. Remission is usually achieved by surgical debulking and chemotherapy, but most (∼70%) of patients ultimately develop treatment-resistant disease. Infiltration of immune cells into the HGSC microenvironment, including natural killer (NK) cells, is associated with lengthened overall and progression-free survival, suggesting that immunosurveillance contributes to HGSC control. The mechanisms permitting or prohibiting anticancer activity are unclear, but if understood, they might shed light on opportunities for immunotherapy or precision medicine. We investigated the interactions between NK cells and adenosine, an immunosuppressive metabolite that concentrates in HGSC. Exposure of HGSC to adenosine induces upregulation of ligands associated with NK cell inhibition, including HLA-E. On NK cells, adenosine induces upregulation of the cognate inhibitory receptor for HLA-E, natural killer group 2A (NKG2A). The CD16low NK cell subset was most responsive to the HGSC cell line, OVCAR4, but also more likely to upregulate NKG2A and become inhibited after adenosine treatment. A single nucleotide polymorphism (SNP) in the gene for NKG2A (V5: rs2734440 C) encodes for higher NKG2A surface expression and a stronger inhibitory response to HLA-E-expressing targets. Here, we demonstrate that NK cell suppression in the context of adenosine is most profound in NK cells homozygous for the V5 variant. Our results reveal a novel link between metabolism and immunologic inhibition and highlight the KLRC1-V5 variant as a putative biomarker for response to anti-NKG2A therapy and/or susceptibility to adenosine-driven immunosuppression.

Natural Killer Cells: the Missing Link in Effective Treatment for High-Grade Serous Ovarian Carcinoma

Ovarian cancer (OC), especially high-grade serous cancer (HGSC), is a highly heterogeneous malignancy with limited options for curative treatment and a high frequency of relapse. Interactions between OC and the immune system may permit immunoediting and immune escape, and current standard of care therapies can influence immune cell infiltration and function within the tumor microenvironment. Natural killer (NK) cells are involved in cancer immunosurveillance and immunoediting and can be activated by therapy, but deliberate approaches to maximize NK cell reactivity for treatment of HGSC are in their infancy. NK cells may be the ideal target for immunotherapy of HGSC. The diverse functions of NK cells, and their established roles in immunosurveillance, make them attractive candidates for more precise and effective HGSC treatment. NK cells' functional capabilities differ because of variation in receptor expression and genetics, with meaningful impacts on their anticancer activity. Studying HGSC:NK cell interactions will define the features that predict the best outcomes for patients with the disease, but the highly diverse nature of HGSC will likely require combination therapies or approaches to simultaneously target multiple, co-existing features of the tumor to avoid tumor escape and relapse. We expect that the ideal therapy will enable NK cell infiltration and activity, reverse immunosuppression within the tumor microenvironment, and enable effector functions against the diverse subpopulations that comprise HGSC.