title: FCGR Polymorphisms Influence Response to IL2 in Metastatic Renal Cell Carcinoma.
abstract: Purpose:Fc-gamma receptors (FCGRs) are expressed on immune cells, bind to antibodies, and trigger antibody-induced cell-mediated antitumor responses when tumor-reactive antibodies are present. The affinity of the FCGR/antibody interaction is variable and dependent uponFCGRpolymorphisms. Prior studies of patients with cancer treated with immunotherapy indicate thatFCGRpolymorphisms can influence antitumor response for certain immunotherapies that act via therapeutically administered mAbs or via endogenous tumor-reactive antibodies induced from tumor antigen vaccines. The previously published "SELECT" trial of high-dose aldesleukin (HD-IL2) for metastatic renal cell carcinoma resulted in an objective response rate of 25%. We evaluated the patients in this SELECT trial to determine whether higher-affinityFCGRpolymorphisms are associated with outcome.Experimental Design:SNPs inFCGR2A, FCGR3A, andFCGR2Cwere analyzed, individually and in combination, for associations between genotype and clinical outcome.Results:When higher-affinity genotypes forFCGR2A, FCGR3A, andFCGR2Cwere considered together, they were associated with significantly increased tumor shrinkage and prolonged survival in response to HD-IL2.Conclusions:Although associations of higher-affinityFCGRgenotype with clinical outcome have been demonstrated with mAb therapy and with idiotype vaccines, to our knowledge, this is the first study to show associations ofFCGRgenotypes with outcome following HD-IL2 treatment. We hypothesize that endogenous antitumor antibodies may engage immune cells through their FCGRs, and HD-IL2 may enhance antibody-induced tumor destruction, or antibody-enhanced tumor antigen presentation, via augmented activation of innate or adaptive immune responses; this FCGR-mediated immune activity would be augmented through immunologically favorable FCGRs.Clin Cancer Res; 23(9); 2159-68. ©2016 AACR.
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Erbe
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Jacob
authors.initials: J
authors.lastname: Goldberg
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Mikayla
authors.initials: M
authors.lastname: Gallenberger
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin.
authors.forename: KyungMann
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin.
authors.forename: Lakeesha
authors.initials: L
authors.lastname: Carmichael
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Dustin
authors.initials: D
authors.lastname: Hess
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin.|Department of Pediatrics, University of Wisconsin, Madison, Wisconsin.
authors.forename: Eneida A
authors.initials: EA
authors.lastname: Mendonca
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin.
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Hank
authors.affiliation: Department of Biostatistics, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Su-Chun
authors.initials: SC
authors.lastname: Cheng
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: The Cytokine Working Group.|Department of Medicine, Georgetown University, Washington DC.
authors.forename: Michael
authors.initials: M
authors.lastname: Atkins
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Alexander
authors.initials: A
authors.lastname: Carlson
authors.affiliation: The Cytokine Working Group.|Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: James W
authors.initials: JW
authors.lastname: Mier
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: David J
authors.initials: DJ
authors.lastname: Panka
authors.affiliation: The Cytokine Working Group.|Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison, Wisconsin. pmsondel@humonc.wisc.edu.|Department of Pediatrics, University of Wisconsin, Madison, Wisconsin.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007376:Interleukin-2 / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG / Q000235:genetics* / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: C445323:FCGR2A protein, human; C000609718:FCGR2C protein, human; C496124:FCGR3A protein, human; D007376:Interleukin-2; D017452:Receptors, IgG; D011994:Recombinant Proteins; C082598:aldesleukin