Implication of the β2-microglobulin gene in the generation of tumor escape phenotypes

Abstract

Classical MHC molecules present processed peptides from endogenous protein antigens on the cell surface, which allows CD8(+) cytotoxic T lymphocytes (CTLs) to recognize and respond to the abnormal antigen repertoire of hazardous cells, including tumor cells. The light chain, β2-microglobulin (β2m), is an essential constant component of all trimeric MHC class I molecules. There is convincing evidence that β2m deficiency generates immune escape phenotypes in different tumor entities, with an exceptionally high frequency in colorectal carcinoma (CRC) and melanoma. Damage of a single β2m gene by LOH on chromosome 15 may be sufficient to generate a tumor cell precommitted to escape. In addition, this genetic lesion is followed in some tumors by a mutation of the second gene (point mutation or insertion/deletion), which produces a tumor cell unable to express any HLA class I molecule. The pattern of mutations found in microsatellite unstable colorectal carcinoma (MSI-H CRC) and melanoma showed a striking similarity, namely the predominance of frameshift mutations in repetitive CT elements. This review emphasizes common but also distinct molecular mechanisms of β2m loss in both tumor types. It also summarizes recent studies that point to an acquired β2m deficiency in response to cancer immunotherapy, a barrier to successful vaccination or adoptive cellular therapy.

Fig. 1

β2m gene alterations in human tumors. Summary of the different β2m gene mutations found in tumor samples and cell lines of melanoma (Me, n = 18), colon cancer (Co, n = 43), Daudi lymphoma (Ly, one case), lung cancer (Lu, 2 cases), sarcomatoid renal carcinoma (Re, 2 cases), cervical cancer (Cer, one case), and testicular diffuse large B cell lymphoma (LyT, 2 cases). The type of mutation is indicated by color according to the legend

Fig. 2

Distribution of frameshift mutations in repeat sequences of the β2m gene in colon cancers (a) and melanoma (b). Schematic codon sequence of the β2m gene. Deletions and insertions both affect mono (A, C) and dinucleotide repeats (CT, CC, TT), but tetranucleotide sequences (CTCT, TCTT, TTCT) are only affected by deletions. In colon tumors (a), deletions and insertions were detected throughout the gene repeat sequences whereas in melanoma samples (b), deletions were only observed in the mutation hotspot of exon 1 (CT repeat sequence)

Fig. 3

Schematic representation of single base substitutions affecting β2m gene in human tumors. Nonsense mutation: a single nucleotide substitution in tumor DNA results in a premature stop codon. Missense mutation: a single nucleotide substitution alters the codon sequence and replace one amino acid by another in the gene product. Finally, a single nucleotide substitution in the splicing acceptor site (AG) activates a new “cryptic splice site” and introduces a premature stop codon

Fig. 4

Schematic representation of a single and a double hit in the β2m gene. In the first example, an MSS colon carcinoma harbors an LOH in the chromosome 15q21 region but retains HLA class I expression (a). In the second example, a melanoma has alterations affecting both β2m genes (an LOH and a point mutation generating a stop codon) leading to a total loss of HLA class I expression (b)