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.
authors: Department of Medicine, University of California, San Francisco, San Francisco, California.
authors: Juan
authors: J
authors: Du
authors: Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, San Francisco, California.
authors: Sandra
authors: S
authors: Lopez-Verges
authors: Alliance Statistics and Data Center, Duke University Medical Center, Durham, North Carolina.
authors: Brandelyn N
authors: BN
authors: Pitcher
authors: Alliance Statistics and Data Center, Duke University Medical Center, Durham, North Carolina.
authors: Jeffrey
authors: J
authors: Johnson
authors: Alliance Statistics and Data Center, Duke University Medical Center, Durham, North Carolina.
authors: Sin-Ho
authors: SH
authors: Jung
authors: Department of Medicine, University of California, San Francisco, San Francisco, California.
authors: Lili
authors: L
authors: Zhou
authors: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: Katharine
authors: K
authors: Hsu
authors: Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York.
authors: Myron S
authors: MS
authors: Czuczman
authors: Department of Medicine, Georgetown University, Washington, District of Columbia.
authors: Bruce
authors: B
authors: Cheson
authors: Department of Medicine, University of California, San Francisco, San Francisco, California.
authors: Lawrence
authors: L
authors: Kaplan
authors: Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, San Francisco, California.
authors: Lewis L
authors: LL
authors: Lanier
authors: Department of Medicine, University of California, San Francisco, San Francisco, California. venstromj@gmail.com.
authors: Jeffrey M
authors: JM
authors: Venstrom
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D054340:Receptors, KIR / Q000276:immunology; D000069283:Rituximab; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D054340:Receptors, KIR; D000069283:Rituximab