Genomic loss of HLA alleles may affect the clinical outcome in low-risk myelodysplastic syndrome patients

Abstract

The Revised International Prognostic Score and some somatic mutations in myelodysplastic syndrome (MDS) are independently associated with transformation to acute myeloid leukemia (AML). Immunity has also been implicated in the pathogenesis of MDS, although the underlying mechanism remains unclear. We performed a SNP array on chromosome 6 in CD34+ purified blasts from 19 patients diagnosed with advanced MDS and 8 patients with other myeloid malignancies to evaluate the presence of loss of heterozygosity (LOH) in HLA and its impact on disease progression. Three patients had acquired copy-neutral LOH (CN-LOH) on 6p arms, which may disrupt antigen presentation and act as a mechanism for immune system evasion. Interestingly, these patients had previously been classified at low risk of AML progression, and the poor outcome cannot be explained by the acquisition of adverse mutations. LOH HLA was not detected in the remaining 24 patients, who all had adverse risk factors. In summary, the clinical outcome of patients with advanced MDS might be influenced by HLA allelic loss, wich allows subclonal expansions to evade cytotoxic-T and NK cell attack. CN-LOH HLA may therefore be a factor favoring MDS progression to AML independently of the somatic tumor mutation load.

Combined Photosensitization and Vaccination Enable CD8 T-Cell Immunity and Tumor Suppression Independent of CD4 T-Cell Help

“…Typically, the protective cellular responses have been ascribed to CD8 T cells, since tumor cells express little, if any, MHC class II molecules (18). Unfortunately, the therapeutic benefits of cancer vaccines are still ambiguous, in part due to immunosuppressive signals produced by the tumors, which also include the down regulation of MHC class I molecules (19). Hence, it is important to develop strategies that trigger strong tumor-specific cytotoxic immune responses, while overcoming potentially immunosuppressive tumor microenvironments.…”

KIR3DL1 and HLA-Bw4 Interaction Showed a Favorable Role in Patients with Myelodysplastic Syndromes in Chinese Southern Han

“…Although no MDS patient showed total loss of HLA class I expression on CD34 + cells in peripheral blood, the HLA class I expression on dysplastic CD34 + cells was significantly lower in MDS patients than that in healthy controls (P = 0:002) [18]. A loss of heterozygosity in the HLA region may be as another possible immunoevasion mechanism in advanced cases of MDS [19]. These specific alterations can result in the inefficient presentation of immunodominant antigens to cytotoxic T lymphocytes but offer a necessary condition for NK cell-mediated immune response.…”

“…The differential effect played by KIR AA genotype in the above three studies might be partly resulted from the distinct maturation stages and the nonoverlapping subsets of lineage markers and fusion proteins, such as HLA class I molecules, expressed by various myeloid neoplasms [16][17][18]. HLA class I expression was normally expressed in CD34 + blasts and during myeloid differentiation in MDS patients; however, the copy-neutral loss of heterozygosity in the HLA region appeared to favor MDS progression to AML and selective downregulation of HLA class I enhanced KIR AA protection against different leukemia types [18][19][20][21].…”

Targeting loss of heterozygosity for cancer-specific immunotherapy

“…Recently, LOH has been implicated as both a resistance mechanism and a negative clinical correlate for immunotherapies ( 113 , 114 ). For example, HLA LOH has been clinically correlated with poor prognosis in several cancer types, is associated with reduced patient survival following immune checkpoint blockade, and provides a pathway for resistance to tumor-infiltrating lymphocyte therapies targeting KRAS G12D and TP53 R175H driver mutation neoantigens ( 97 , 115 – 121 ). In such instances, HLA allelic loss presumably reflects genetic loss of the HLA restriction element responsible for presenting the dominant cancer-targeting antigens required to mount an effective antitumor immune response.…”