American Association for Cancer Research
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Supplemental Figure 5 from CALGB 150905 (Alliance): Rituximab Broadens the Antilymphoma Response by Activating Unlicensed NK Cells

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posted on 2023-04-03, 23:02 authored by Juan Du, Sandra Lopez-Verges, Brandelyn N. Pitcher, Jeffrey Johnson, Sin-Ho Jung, Lili Zhou, Katharine Hsu, Myron S. Czuczman, Bruce Cheson, Lawrence Kaplan, Lewis L. Lanier, Jeffrey M. Venstrom

IL-2 stimulation of unlicensed NK cell degranulation.



Natural killer (NK) cells contribute to clinical responses in patients treated with rituximab, but the rules determining NK-cell responsiveness to mAb therapies are poorly defined. A deeper understanding of the mechanisms responsible for antibody-dependent cellular cytotoxicity (ADCC) could yield useful biomarkers for predicting clinical responses in patients. Unlicensed NK cells, defined as NK cells lacking expression of an inhibitory KIR for self-HLA class I ligands, are hyporesponsive in steady state, but are potent effectors in inflammatory conditions. We hypothesized that antitumor antibodies such as rituximab can overcome NK-cell dependence on licensing, making unlicensed NK cells important for clinical responses. Here, we examined the influences of variations in KIR and HLA class I alleles on in vitro responses to rituximab. We tested the clinical significance in a cohort of patients with follicular lymphoma treated with rituximab-containing mAb combinations, and show that rituximab triggers responses from all NK-cell populations regardless of licensing. Neither IL2 nor accessory cells are required for activating unlicensed NK cells, but both can augment rituximab-mediated ADCC. Moreover, in 101 patients with follicular lymphoma treated with rituximab-containing mAb combinations, a “missing ligand” genotype (predictive of unlicensed NK cells) is associated with a higher rate of progression-free survival. Our data suggest that the clinical efficacy of rituximab may be driven, in part, by its ability to broaden the NK-cell repertoire to include previously hyporesponsive, unlicensed NK cells. A “missing ligand” KIR and HLA class I genotype may be predictive of this benefit and useful for personalizing treatment decisions in lymphomas and other tumors. Cancer Immunol Res; 2(9); 878–89. ©2014 AACR.

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