FCGR Polymorphisms Influence Response to IL2 in Metastatic Renal Cell Carcinoma

Abstract

Background Fc-gamma receptors (FCGRs) are expressed on immune cells, bind to antibodies, and trigger antibody-induced cell-mediated anti-tumor responses when tumor-reactive antibodies are present. The affinity of the FCGR/antibody interaction is variable and dependent upon FCGR polymorphisms. Prior studies of cancer patients treated with immunotherapy indicate that FCGR 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 (mRCC) resulted in an objective response rate (ORR) of 25%. We evaluated the patients in this SELECT trial to determine whether higher affinity FCGR polymorphisms are associated with outcome. Methods Single nucleotide polymorphisms (SNPs) in FCGR2A, FCGR3A, and FCGR2C were analyzed, individually and in combination, for associations between genotype and clinical outcome. Results When higher affinity genotypes for FCGR2A, FCGR3A and FCGR2C were considered together, they were associated with significantly increased tumor shrinkage and prolonged survival in response to HD-IL2. Conclusions While associations of higher affinity FCGR 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 FCGR genotypes with outcome following HD-IL2 treatment. We hypothesize that endogenous anti-tumor 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.

HLA-Bw4-I-80 Isoform Differentially Influences Clinical Outcome As Compared to HLA-Bw4-T-80 and HLA-A-Bw4 Isoforms in Rituximab or Dinutuximab-Based Cancer Immunotherapy

“…FCGR polymorphisms can alter the affinity of FCGRs for the Fc portion of antibodies (mAbs or endogenous antibodies) ( 37 ). For example, in a separate study of patients with metastatic renal cell carcinoma treated with high-dose IL-2, we found that patients with a “higher affinity” FCGR genotype had improved clinical outcome as compared to those patients with a “lower affinity” FCGR genotype ( 38 ). In our analysis of those same metastatic renal cell carcinoma patients for KIR/KIR-ligand genotype influence on outcome, we did not observe differences in clinical outcome associated with KIR3DL1 and HLA-Bw4 genotype status ( 39 ).…”

Screening Potential Prognostic Factors for gastric carcinoma and Indicators for Tumor Microenvironment Remodeling in Female and Male patients Based on TCGA Data Mining

“…It had two polymorphic alleles at the amino acid position, which was associated with an increased risk of GC patients [20]. Clinical studies have reported that FCGR2A polymorphisms are associated with the clinical outcome of tumours, including colorectal cancer, neuroblastoma and renal cell carcinoma [21][22][23][24]. In contrast, either FCGR2A or FCGR3A polymorphisms affect the clinical outcome of follicular lymphoma patients [25].…”

NK Cell-Based Immunotherapy in Renal Cell Carcinoma

“…In fact, high doses of IL-2 were approved by the FDA in 1992 to treat patients with metastatic RCC [78,193]. Evaluating data from a cohort of patients treated with high doses of IL-2, it was found that when the higher-affinity genotypes for FCGR2A, FCGR3A, and FCGR2C were considered together, they were associated with increased tumor shrinkage and prolonged survival [194]. FCGR3A encodes for CD16 expressed on NK cells.…”