Ricerc@Sapienza

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 ?2 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.