IRF5 gene polymorphisms in melanoma

Abstract

BackgroundInterferon regulatory factor (IRF)-5 is a transcription factor involved in type I interferon signaling whose germ line variants have been associated with autoimmune pathogenesis. Since relationships have been observed between development of autoimmunity and responsiveness of melanoma to several types of immunotherapy, we tested whether polymorphisms of IRF5 are associated with responsiveness of melanoma to adoptive therapy with tumor infiltrating lymphocytes (TILs).Methods140 TILs were genotyped for four single nucleotide polymorphisms (rs10954213, rs11770589, rs6953165, rs2004640) and one insertion-deletion in the IRF5 gene by sequencing. Gene-expression profile of the TILs, 112 parental melanoma metastases (MM) and 9 cell lines derived from some metastases were assessed by Affymetrix Human Gene ST 1.0 array.ResultsLack of A allele in rs10954213 (G > A) was associated with non-response (p < 0.005). Other polymorphisms in strong linkage disequilibrium with rs10954213 demonstrated similar trends. Genes differentially expressed in vitro between cell lines carrying or not the A allele could be applied to the transcriptional profile of 112 melanoma metastases to predict their responsiveness to therapy, suggesting that IRF5 genotype may influence immune responsiveness by affecting the intrinsic biology of melanoma.ConclusionsThis study is the first to analyze associations between melanoma immune responsiveness and IRF5 polymorphism. The results support a common genetic basis which may underline the development of autoimmunity and melanoma immune responsiveness.

Non-BRAF-targeted therapy, immunotherapy, and combination therapy for melanoma

“…In the first one, we hypothesized that polymorphisms of IRF5 gene, known to be implicated in autoimmune diseases and in particular to systemic lupus erythematosus, might play a role in the immune-mediated rejection of the tumor. Concordant to our hypothesis, we were able to show that the IRF5 genetic variants protecting against the development of autoimmunity were highly predictive of nonresponsiveness to adoptive therapy in melanoma [131]. These results support the link between autoimmunity and immune responsiveness.…”

“…The rather disappointing results of cancer vaccines could be due to a mixture of the following factors: i) the presence of a highly immunosuppressive microenvironment with consequent inability of T cells to overcome environmental immunosuppression in absence of co-stimulatory or anti-inhibitory stimuli [126]; ii) the scant ability of antitumor T cells to localize at tumor site [127][128][129]; iii) the rapid senescence of tumor-specific T cells or T-cell repertoire [122,130]; iv) the highly mutable tumor target capable of immune-evasion and antigen loss [122]; and v) the presence of unfavorable genetic condition (host polymorphisms or cancer mutations) [129,131,132] or unfavorable environmental factors (unintact commensale gut microbiota) [118] that can negatively switch the balance between tolerance and acute (therapeutic) inflammation. The BRAF inhibitor curves were approximated from the vemurafenib and dabrafenib randomized Phase III trials.…”

Innate and adaptive immune cells in the tumor microenvironment

“…112). A recently identified IRF5 polymorphism was associated with clinical response to tumor-infiltrating lymphocyte adoptive therapy in melanoma 113 .…”

Cancer Stem-like Cells Derived from Chemoresistant Tumors Have a Unique Capacity to Prime Tumorigenic Myeloid Cells

“…Moreover, deletions of chromosome 7q32 are associated with downregulation of IRF5 function, disease progression, and poor prognosis in patients with marginal zone lymphoma. Genetic polymorphisms of IRF5 may serve as biomarkers to predict clinical responses to immunotherapy and chemotherapy in patients with melanoma and hematologic malignancies, respectively (22)(23)(24).…”