Abstract
BackgroundAbnormalities in Human Leukocyte Antigen (HLA) class I expression are common in colorectal cancer. Since HLA expression is required to activate tumor antigen-specific cytotoxic T-lymphocytes (CTL), HLA class I abnormalities represent a mechanism by which tumors circumvent immune surveillance. Tumors with high microsatellite instability (MSI-H) are believed to face strong selective pressure to evade CTL activity since they produce large amounts of immunogenic peptides. Previous studies identified the prevalence of HLA class I alterations in MSI-H tumors. However, those reports did not compare the frequency of alterations between hereditary and sporadic MSI-H tumors neither the mechanisms that led to HLA class I alterations in each subgroup.MethodsTo characterize the HLA class I expression among sporadic MSI-H and microsatellite-stable (MSS) tumors, and HNPCC tumors we compared immunohistochemically the expression of HLA class I, β2-microglobulin (β2m), and Antigen Processing Machinery (APM) components in 81 right-sided sporadic and 75 HNPCC tumors. Moreover, we investigated the genetic basis for these changes.ResultsHLA class I loss was seen more frequently in MSI-H tumors than in MSS tumors (p < 0.0001). Distinct mechanisms were responsible for HLA class I loss in HNPCC and sporadic MSI-H tumors. Loss of HLA class I expression was associated with β2m loss in HNPCC tumors, but was correlated with APM component defects in sporadic MSI-H tumors (p < 0.0001). In about half of the cases, loss of expression of HLA class I was concordant with the detection of one or more mutations in the β2m and APM components genes.ConclusionHLA class I aberrations are found at varying frequencies in different colorectal tumor types and are caused by distinct genetic mechanisms. Chiefly, sporadic and hereditary MSI-H tumors follow different routes toward HLA class I loss of expression supporting the idea that these tumors follow different evolutionary pathways in tumorigenesis. The resulting variation in immune escape mechanisms may have repercussions in tumor progression and behavior.
Highlights
Abnormalities in Human Leukocyte Antigen (HLA) class I expression are common in colorectal cancer
In order to compare the expression of HLA class I in sporadic MSI-H and MSS right sided tumors (RST) and hereditary non-polyposis colorectal cancer (HNPCC) MSI-H cases, we used an antibody panel recognizing monomorphic determinants expressed on HLA class I heavy chains, β2m and Antigen Processing Machinery (APM) components (Figure 1)
Loss of HLA class I expression was more often associated with that of one of the APM components, occurring in about 37% of HLA-negative tumors regardless of their mismatch repair status (Table 2). β2m loss was only found in one HLA class I negative MSI-H sporadic tumor that interestingly presented loss of the APM molecules TAP2, Calreticulin and Tapasin (Figure 2)
Summary
Abnormalities in Human Leukocyte Antigen (HLA) class I expression are common in colorectal cancer. Since HLA expression is required to activate tumor antigen-specific cytotoxic Tlymphocytes (CTL), HLA class I abnormalities represent a mechanism by which tumors circumvent immune surveillance. Tumor cells may elicit cytotoxic T-lymphocyte (CTL)-mediated immune responses– partly a consequence of accumulated gene mutations that are translated into altered peptides [1]. Multiple mechanisms have been shown to underlie defects in HLA class I expression by tumor cells They include mutations in the individual HLA class I genes HLA-A, -B and -C, located on chromosome 6p21.3) [5]; mutations in β2microglobulin (β2m) [6,7,8,9], molecule required for cell surface expression of HLA class I antigens; and defects in components of the HLA class I-associated antigenprocessing machinery (APM) [9,10,11]. The immunoproteasome generates peptides mostly, not exclusively from endogenous proteins, TAP1 and TAP2 facilitate peptide translocation from the cytosol into the lumen of the endoplasmic reticulum, where the peptides are loaded onto the HLA class I molecules with the aid from the several chaperones [12]
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