Reference Detail

Ref Type

Journal Article

PMID

(16648140)

Authors

Chang CC, Ogino T, Mullins DW, Oliver JL, Yamshchikov GV, Bandoh N, Slingluff CL Jr, Ferrone S

Title

Defective human leukocyte antigen class I-associated antigen presentation caused by a novel beta2-microglobulin loss-of-function in melanoma cells.

Journal	Vol	Issue	Date	Pages	Journal Short Title
The Journal of biological chemistry	281	27	2006 Jul 7	18763-73	J Biol Chem

URL

Abstract Text

The major histocompatibility complex class I molecules consist of three subunits, the 45-kDa heavy chain, the 12-kDa beta(2)-microglobulin (beta(2)m), and an approximately 8-9-residue antigenic peptide. Without beta(2)m, the major histocompatibility complex class I molecules cannot assemble, thereby abolishing their transport to the cell membrane and the subsequent recognition by antigen-specific T cells. Here we report a case of defective antigen presentation caused by the expression of a beta(2)m with a Cys-to-Trp substitution at position 25 (beta(2)m(C25W)). This substitution causes misfolding and degradation of beta(2)m(C25W) but does not result in complete lack of human leukocyte antigen (HLA) class I molecule expression on the surface of melanoma VMM5B cells. Despite HLA class I expression, VMM5B cells are not recognized by HLA class I-restricted, melanoma antigen-specific cytotoxic T lymphocytes even following loading with exogenous peptides or transduction with melanoma antigen-expressing viruses. Lysis of VMM5B cells is restored only following reconstitution with exogenous or endogenous wild-type beta(2)m protein. Together, our results indicate impairment of antigenic peptide presentation because of a dysfunctional beta(2)m and provide a mechanism for the lack of close association between HLA class I expression and susceptibility of tumor cells to cytotoxic T lymphocytes-mediated lysis in malignant diseases.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
B2M	C45W	missense	loss of function - predicted	B2M C45W lies within the Ig-like C1-type domain of the B2m protein (UniProt.org). C45W results in the loss of the disulfide bond between C45 and C100 (PMID: 16648140), increased degradation of B2m, down regulation of HLA class I molecules, and defects in antigen presentation in cultured cells (PMID: 16648140), and therefore, is predicted to result in a loss of B2m protein function.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
B2M C45W	melanoma	resistant	Interferon gamma	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring B2M C45W displayed greatly reduced expression of HLA class I molecules, which was not corrected by treatment with interferon gamma (PMID: 16648140).	16648140