HNPCC versus sporadic microsatellite-unstable colon cancers follow different routes toward loss of HLA class I expression

Abstract

Background: 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. 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.

Immunoprofiles of colorectal cancer from Lynch syndrome

“…related to deregulation of MHC class I expression, apply between sporadic and hereditary MSI tumors, and motivate mechanistic explanation related to the variable response rates observed in sporadic and Lynch syndrome-associated MSI tumors treated with anti-PD-1 inhibitors. 11,15 Defining the immunogenic environment and immune evasion mechanisms in Lynch syndrome, we hypothesize that Lynch syndrome tumors could develop resistance to anti-PD-1 therapy by bypassing the PD-L1/PD-1 pathway. In Lynch syndrome, 76% of the tumors showed up-regulation of PD-L1, indicating potential response to anti-PD-1 therapy.…”

“…Loss of B2M was, however, observed in 28% and may result in loss of MHC class I presentation and confer decreased sensitivity to therapies directed at cytotoxic T cells, such as anti-PD-1 therapies. 11,13,15,17 …”

“…8,20–22 Loss of B2M in 28% of the Lynch syndrome tumors was within previous reported range of 21–30% and are likely caused by frameshift mutations in microsatellite regions of the B2M gene (Figure 1). 13,15 The tumorigenic event of B2M loss is likely occurring in the middle of the adenoma-carcinoma sequence since B2M loss has not been found in metastasizing tumors or MMR deficient adenomas. 13,23 The prognostic value of B2M has been investigated in several studies with contradicting results.…”

“…Subgroup analyses linked B2M loss with low levels of MHC class I related genes supporting previous studies. 13,15 Loss of B2M and subsequent lack of MHC class I may affect the level of CD8 cells and, in contrast, attract and activate the natural killer cell-mediated apoptosis, supported by the upregulation of Caspase 3 and the natural killer cell inhibitory ligand KIR2DL1 (Figure 3). The involvement of natural killer cells may offer an explanation to the favorable prognosis in B2M negative tumors though validation of the molecular profiles and the prognostic implications are needed.…”

“…13,14 B2M loss has been associated with loss of MHC class I receptors suggesting that this subset may not elicit neoepitope-induced T cell responses. 4,15 In contrast, high levels of PD-L1 have been associated with T cell exhaustion that can be reversed by inhibition of the programmed death 1 (PD-1)/PD-L1 binding. 16 As a basis for preselection of patients, who may benefit from immunotherapy, we characterized the immunophenotypes and transcriptional immune profiles in Lynch syndrome versus MMR proficient colorectal cancers from the familial colorectal cancer type X (FCCTX) syndrome.…”