The role of AIRE polymorphisms in melanoma

Abstract

Polymorphisms of AIRE, a transcription factor that up-regulates intrathymic expression of tissue-specific antigens including melanoma-associated antigens (MAAs), may variably affect the selection of MAAs-specific thymocytes, generating T-cell repertoires protecting or predisposing individuals to melanoma. We found that AIRE single nucleotide polymorphisms (SNPs) rs1055311, rs1800520 and rs1800522 were significantly more frequent in healthy subjects than in melanoma patients, independently from sex, age and stages of melanoma. The presence of these SNPs was associated with increased frequency of two T-cell clonotypes specific for MAGE-1 linking their protective effect to selection/expansion of MAA-specific T cells. Interestingly, mRNA transcribed on the rs1800520 SNP showed increased free energy than the wild type suggesting that its reduced stability may be responsible for the different activity of the polymorphic AIRE molecule. This finding may contribute at identifying subjects with increased risk of developing melanoma or patients with melanoma that may take benefit from immunotherapy.

Inflammatory-Related Genetic Variants in Non–Muscle-Invasive Bladder Cancer Prognosis: A Multimarker Bayesian Assessment

“…Those T regulators are thought to be major barrier impeding antitumor immune response (42). In melanoma, polymorphisms in AIRE may variably affect the selection of melanoma-associated antigen-specific thymocytes, generating T-cell repertoires protecting or predisposing individuals to cancer (43). CARD4/NOD1 is a member of the NOD receptor family that plays a major role in innate and adaptive immunities.…”

AIRE expands: new roles in immune tolerance and beyond

“…These findings are likely to translate to patients, since human mTECs express a large number of known melanoma antigens 69 . Furthermore, case-control studies have associated melanoma protection with Aire polymorphisms that decrease Aire expression 70 .…”

Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity

“…All 79 patients included in this study were randomized to the ipilimumab-alone arm. The rs1055311 TT polymorphism, which has previously been associated with protection from melanoma development (12), was present in 6 of 79 patients (7.6%). The presence of the rs1055311 TT polymorphism was associated with increased probability of progression-free survival (Fisher's exact test, P = 0.036; Figure 1C) and trended toward increased probability of overall survival, although this did not reach statistical significance (log rank P = 0.13; Figure 1D).…”

“…However, only 10%-20% of patients respond to treatment (2,20,21), and the factors that determine response are unclear. Multiple Aire polymorphisms, including one that may negatively affect mRNA Aire stability (12), have been associated with protection from melanoma development. This suggested that Aire polymorphisms that disrupt Aire function may enhance antimelanoma immunity in humans.…”

“…As a consequence, while purging self-reactive T cells that recognize melanocyte antigens, Aire also removes T cells capable of recognizing and eradicating melanoma cells. In humans, protection from melanoma has been associated with distinct AIRE single nucleotide polymorphisms (SNPs), which can decrease stability of Aire mRNA (12). This protection is associated with increased frequency of T cell clones recognizing MAGE-1, a self/melanoma antigen expressed in the thymus.…”