FCGR Polymorphisms Influence Response to IL2 in Metastatic Renal Cell Carcinoma.

Abstract

<b>Purpose:</b> 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 upon <i>FCGR</i> polymorphisms. Prior studies of patients with cancer treated with immunotherapy indicate that <i>FCGR</i> polymorphisms 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-affinity <i>FCGR</i> polymorphisms are associated with outcome.<b>Experimental Design:</b> SNPs in <i>FCGR2A, FCGR3A</i>, and <i>FCGR2C</i> were analyzed, individually and in combination, for associations between genotype and clinical outcome.<b>Results:</b> When higher-affinity genotypes for <i>FCGR2A, FCGR3A</i>, and <i>FCGR2C</i> were considered together, they were associated with significantly increased tumor shrinkage and prolonged survival in response to HD-IL2.<b>Conclusions:</b> Although associations of higher-affinity <i>FCGR</i> genotype with clinical outcome have been demonstrated with mAb therapy and with idiotype vaccines, to our knowledge, this is the first study to show associations of <i>FCGR</i> genotypes 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. <i>Clin Cancer Res; 23(9); 2159-68. ©2016 AACR</i>.