MUTYH-associated polyposis carcinomas frequently alter HLA class I expression as an immune-evasive mechanism
N.F.C.C. de Miranda1, M. Nielsen2, A. Middeldorp1, M. van Puijenbroek1, T. van Wezel1, F.J. Hes2, H. Morreau1
Department of Pathology, Leiden University Medical Center1; Department of Clinical Genetics, Leiden University Medical Center2
Background & Aims: Abnormalities in HLA class I expression occur frequently in colorectal cancers bearing mismatch repair (MMR) deficiency, and are interpreted as immune evasion mechanisms. MUTYH-associated polyposis (MAP) is a colorectal cancer syndrome caused by defects in the MUTYH DNA repair enzyme. We aimed to describe, for the first time, the frequency of HLA class I alterations in MAP carcinomas and compare it to the ones observed in MMR deficient colorectal tumors.
Methods: To characterize HLA class I expression in MAP carcinomas we detected immunohistochemically HLA class I, β2-microglobulin (β2m), and antigen processing machinery molecules, in 47 carcinomas from MAP patients. Furthermore, we investigated the occurrence of loss of heterozygosity (LOH) at 6p21 (HLA class I loci), 15q21-22.2 (β2m locus) and sequenced the β2m gene. We also characterized and compared the lymphocytic infiltrate between tumors with distinct HLA class I phenotypes.
Results: HLA class I expression abnormalities were detected in 58% of primary MAP carcinomas and 89% of tumor metastases and presented frequently together with β2m deficiencies. Additionally, a higher amount of cytotoxic T-cells was present in tumors bearing HLA class I expression alterations.
Conclusions: HLA class I expression abnormalities occur frequently in MAP carcinomas, similarly to MMR deficient colorectal tumors, providing additional evidence for a link between DNA repair deficiencies and the need for tumors to adopt immune evasion mechanisms. This demonstration of an active immune response during tumor progression could represent an opportunity for the development of vaccines and memory T-cell-based diagnostic assays.