The tumour suppressor Fhit positively regulates MHC class I expression on cancer cells

Abstract

MHC class I (MHC‐I) molecules are ubiquitously expressed on the cells of an organism. Study of the regulation of these molecules in normal and disease conditions is important. In tumour cells, the expression of MHC‐I molecules is very frequently lost, allowing these cells to evade the immune response. Cancers of different histology have shown total loss of MHC‐I molecule expression, due to a coordinated transcriptional down‐regulation of various antigen‐processing machinery (APM) components and/or MHC‐I heavy chains. The mechanisms responsible for these alterations remain unclear. We determined the possible genes involved by comparing MHC‐I‐positive with MHC‐I‐negative murine metastases derived from the same fibrosarcoma tumour clone. MHC‐I‐negative metastases showed transcriptional down‐regulation of APM and MHC‐I heavy chains. The use of microarrays and subtraction cDNA libraries revealed four candidate genes responsible for this alteration, but two of them were ruled out by real‐time RT‐PCR analyses. The other two genes, AP‐2α and Fhit tumour suppressors, were studied by using siRNA to silence their expression in a MHC‐I‐positive metastatic cell line. AP‐2α inhibition did not modify transcriptional expression of APM components or MHC‐I heavy chains or surface expression of MHC‐I. In contrast, silencing of the Fhit gene produced the transcriptional down‐regulation of APM components and MHC‐I heavy chains and decreased MHC‐I surface expression. Moreover, transfection of Fhit in MHC‐I‐negative tumour cell lines restored MHC‐I cell surface expression. These data indicate that defects in Fhit expression may promote MHC‐I down‐regulation in cancer cells and allow escape from immunosurveillance#. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

T Lymphocytes Restrain Spontaneous Metastases in Permanent Dormancy

“…However, other subpopulations of T cells should also be implicated, because the results found in CD8-versus asialo GM1-depleted tumor-bearing mice were different. In addition, we would highlight that MHC-I molecules can act directly as tumor suppressor genes, arresting cancer cell proliferation (48), and the FHIT tumor suppressor gene is directly implicated in MHC-I cell surface expression (30). Taken together, these results suggest that the expression of MHC-I molecules on these metastatic cells may promote the dormant state via immunomediated and oncogenic suppression mechanisms.…”

“…Real-time quantitative PCR analyses were carried out in the 7500 Fast System (Applied Biosystems), performing PCR reactions in quadruplicate and expressing the values obtained as means AE SD. Quantitative PCR was performed with the Power SYBR Green Master Mix (Applied Biosystems); the primers and amplicon size for each gene were previously reported (30). GADPH and b-actin genes were used as housekeeping genes.…”

Specific cellular immune response elicited by the necrotic tumor cell-stimulated macrophages

“…Most tumor cells are deficient MHC Class I molecules, which are the main reason for tumor cells and could not elicit specific immune responses [19]. The decreased or insufficient MHC Class I expression is an important mechanism of tumors escaping from T cellmediated immune responses [20]. Antigen presenting cells, dendritic cells and macrophages are normally expressed as MHC Class I molecules.…”

Metastases in Immune-Mediated Dormancy: A New Opportunity for Targeting Cancer

“…An increase in MHC-I can be achieved with chemotherapy (e.g., 5-aza-2 0 -deoxicytidine, anthracyclines, histone deacetylation inhibitors) and with radiotherapy (50,51). Loss of Fhit tumor suppressor gene expression was recently implicated in the coordinated transcriptional downregulation of APM components, MHC-I heavy chains, and b 2 -microglobulin genes, leading to partial or total losses of MHC-I surface expression on tumor cells (52). Hence, treatments to recover Fhit expression (e.g., demethylating agents or Fhit gene transfection) may also increase MHC-I surface expression in tumors with this defect.…”