CALGB 150905 (Alliance): Rituximab broadens the antilymphoma response by activating unlicensed NK cells Journal Article


Authors: Du, J.; Lopez-Verges, S.; Pitcher, B. N.; Johnson, J.; Jung, S. H.; Zhou, L. L.; Hsu, K.; Czuczman, M. S.; Cheson, B.; Kaplan, L.; Lanier, L. L.; Venstrom, J. M.
Article Title: CALGB 150905 (Alliance): Rituximab broadens the antilymphoma response by activating unlicensed NK cells
Abstract: 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. (C)2014 AACR.
Keywords: follicular lymphoma; mhc class-i; self-mhc; non-hodgkins-lymphoma; peripheral-blood; t-cells; monoclonal-antibody therapy; natural-killer-cells; clinical-response; expressing inhibitory kir
Journal Title: Cancer Immunology Research
Volume: 2
Issue: 9
ISSN: 2326-6066
Publisher: American Association for Cancer Research  
Date Published: 2014-09-01
Start Page: 878
End Page: 889
Language: English
ACCESSION: WOS:000346133700007
DOI: 10.1158/2326-6066.cir-13-0158
PROVIDER: wos
PMCID: PMC4264658
PUBMED: 24958280
Notes: Article -- Source: Wos
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  1. Katharine C Hsu
    149 Hsu