MICA-129 Dimorphism and Soluble MICA Are Associated With the Progression of Multiple Myeloma

Abstract

Natural killer (NK) cells are immune innate effectors playing a pivotal role in the immunosurveillance of multiple myeloma (MM) since they are able to directly recognize and kill MM cells. In this regard, among activating receptors expressed by NK cells, NKG2D represents an important receptor for the recognition of MM cells, being its ligands expressed by tumor cells, and being able to trigger NK cell cytotoxicity. The MHC class I-related molecule A (MICA) is one of the NKG2D ligands; it is encoded by highly polymorphic genes and exists as membrane-bound and soluble isoforms. Soluble MICA (sMICA) is overexpressed in the serum of MM patients, and its levels correlate with tumor progression. Interestingly, a methionine (Met) to valine (Val) substitution at position 129 of the α2 heavy chain domain classifies the MICA alleles into strong (MICA-129Met) and weak (MICA-129Val) binders to NKG2D receptor. We addressed whether the genetic polymorphisms in the MICA-129 alleles could affect MICA release during MM progression. The frequencies of Val/Val, Val/Met, and Met/Met MICA-129 genotypes in a cohort of 137 MM patients were 36, 43, and 22%, respectively. Interestingly, patients characterized by a Val/Val genotype exhibited the highest levels of sMICA in the sera. In addition, analysis of the frequencies of MICA-129 genotypes among different MM disease states revealed that Val/Val patients had a significant higher frequency of relapse. Interestingly, NKG2D was downmodulated in NK cells derived from MICA-129Met/Met MM patients. Results obtained by structural modeling analysis suggested that the Met to Val dimorphism could affect the capacity of MICA to form an optimal template for NKG2D recognition. In conclusion, our findings indicate that the MICA-129Val/Val variant is associated with significantly higher levels of sMICA and the progression of MM, strongly suggesting that the usage of soluble MICA as prognostic marker has to be definitely combined with the patient MICA genotype.

Tumor-Derived Soluble MICA Obstructs the NKG2D Pathway to Restrain NK Cytotoxicity

“…Here we showed that a high level of soluble sMICA, an NKG2D ligand, in sera of HCC patients was associated with poor outcome. Wan and his team [35] reported that MICA is released into circulation due to shedding of MICA from cell membranes during tumor transformation or upon stress. We showed that sMICA binds to cells expressing the NKG2D receptor but does not activate NKG2D receptor-mediated signaling and does not activate of NK cells [25].…”

MICA‐129 Met/Val polymorphism could be a genetic biomarker for Familial Breast Cancer in the Tunisian population

“…Met/Val (rs 1051792) polymorphism effect has been largely investigated for their role in infections, autoimmune diseases and cancer, including breast cancer and multiple myeloma (Boukouaci et al, 2009;Campillo et al, 2015;Douik et al, 2009;Isernhagen et al, 2015;Ouni et al, 2017;Raache et al, 2012;Zingoni et al, 2018). These data highlighted the important role played by this polymorphism in tumour escape from the immune system and consequently on breast cancer development.…”

Hitting More Birds with a Stone: Impact of TGF-β on ILC Activity in Cancer

“…However, suppressive functions of TGF-β could be exerted also when the cytokine is not released in its soluble form but associated to exosomes, nanometer-sized vesicles actively secreted by different cell types, including tumor cells. Cancer cell-derived exosomes expressing TGF-β can downregulate NKG2D expression on NK and CD8+ T cells, while other receptors, including CD4, CD8, CD56, CD16, CD69, and CD94 are not affected, indicating the selectivity of the effect [44][45][46][47].…”