Genetic Variants of the NKG2C/HLA-E Receptor-Ligand Axis Are Determinants of Progression-Free Survival and Therapy Outcome in Aggressive B-Cell Lymphoma.

Simple Summary NKG2C and its ligand HLA-E represent key molecules for NK cell-mediated immune responsiveness. However, the impact of genetic variants in NKG2C and HLA-E on clinical outcomes of aggressive B-cell non-Hodgkin lymphoma patients (B-NHL) has not been clarified. In this study, we analyzed the distribution of NKG2C deletion status and HLA-E variants in 441 patients and 192 healthy individuals. Homozygous deletion of NKG2C (NKG2C(-/-)) was more often found in high-risk patients compared to patients with a lower risk and consequently was associated with reduced 2-year progression-free survival. The HLA-E*01:01 allele frequency was increased in B-NHL patients and was strongly related with complete remission. Our results show that absence of NKG2C and HLA-E allelic variations is predictive for B-NHL outcome; while carriers of HLA-E*01:01 are characterized by high, complete remission rates, NKG2C(-/-) was rare, but associated with poorer outcome. Prospective validation of our results identifies patients that may benefit from risk-adapted therapy. Aggressive B-cell lymphomas account for the majority of non-Hodgkin lymphomas (B-NHL). NK cells govern the responses to anti-CD20 monoclonal antibodies and have emerged as attractive targets for immunotherapy in subtypes of B-NHL. NKG2C and its cognate ligand HLA-E represent key molecules for fine-tuning of NK cell-mediated immune responses. Here, we investigated the impact of genetic variants of NKG2C and HLA-E on clinical outcomes of 441 B-NHL patients. Homozygous deletion of NKG2C (NKG2C(-/-)) was three-fold increased in patients compared to 192 healthy controls. Among studied patients, NKG2C(-/-) was more abundant in International Prognostic Index (IPI) high-risk patients compared to patients with a lower IPI (p = 0.013). Strikingly, NKG2C(-/-) was associated with a significantly reduced 2-year PFS (progression-free survival) (p = 0.0062) and represented an independent risk factor for 2-year PFS in multivariate analysis (p = 0.005). For HLA-E, the cognate ligand of NKG2C, the HLA-E*01:01 allele frequency was increased in B-NHL patients compared to controls (p = 0.033) and was associated with complete remission in univariate (p = 0.034) and multivariate (p = 0.018) analysis. Our data suggest that NKG2C and HLA-E genotyping is a promising tool for both defining risk groups of aggressive B-NHL and predicting response to immune therapeutic approaches.