Abstract
The capacity of cytotoxic-T lymphocytes to recognize and destroy tumor cells depends on the surface expression by tumor cells of MHC class I molecules loaded with tumor antigen peptides. Loss of MHC-I expression is the most frequent mechanism by which tumor cells evade the immune response. The restoration of MHC-I expression in cancer cells is crucial to enhance their immune destruction, especially in response to cancer immunotherapy. Using mouse models, we recovered MHC-I expression in the MHC-I negative tumor cell lines and analyzed their oncological and immunological profile. Fhit gene transfection induces the restoration of MHC-I expression in highly oncogenic MHC-I-negative murine tumor cell lines and genes of the IFN-γ transduction signal pathway are involved. Fhit-transfected tumor cells proved highly immunogenic, being rejected by a T lymphocyte-mediated immune response. Strikingly, this immune rejection was more frequent in females than in males. The immune response generated protected hosts against the tumor growth of non-transfected cells and against other tumor cells in our murine tumor model. Finally, we also observed a direct correlation between FHIT expression and HLA-I surface expression in human breast tumors. Recovery of Fhit expression on MHC class I negative tumor cells may be a useful immunotherapeutic strategy and may even act as an individualized immunotherapeutic vaccine.
Highlights
The role of immune system in the control and destruction of tumor cells is well documented [1,2].treatments to activate the immune response against cancer cells or reverse tumor-promoted immunosuppression have produced tumor regression in cancer patients and have been approved for clinical application [3,4,5]
Because these genes and MHC class I (MHC-I) surface expression can be induced by in vitro IFN-γ treatment of these cells, we studied the effect of fragile histidine triad (Fhit) gene transfection on genes of the IFN-γ signal transduction pathway and its role in this induction
The results showed that primary tumors generated from B9 or B11 tumor cells only grew in all animals depleted of CD8-T-cells, indicating that cytotoxic T-lymphocytes are involved in the immune rejection of untransfected tumor cells
Summary
The role of immune system in the control and destruction of tumor cells is well documented [1,2].treatments to activate the immune response against cancer cells or reverse tumor-promoted immunosuppression have produced tumor regression in cancer patients and have been approved for clinical application [3,4,5]. The role of immune system in the control and destruction of tumor cells is well documented [1,2]. The success of many of these immunotherapies requires expression on the tumor cell surface of MHC class I (MHC-I). Molecules loaded with specific tumor antigens [8,9,10]. Loss of this expression is the most frequent immune escape mechanism for cancer cells. Seven altered MHC-I phenotypes described in human tumors may allow cancer cells to be invisible to the immune system (immunoblindness) [11,12]; these phenotypes range from MHC-I allelic losses and MHC-I haplotype loss to the complete loss of expression of all six HLA class I molecules. The molecular mechanisms involved in these MHC-I alterations can be divided between: (a) irreversible mechanisms (“hard lesions”), including genetic changes in HLA class I heavy chains, antigen processing and presentation machinery (APM) components, or β2 -microglobulin, or in other genes related to their expression; and (b) reversible mechanisms (“soft lesions”), including epigenetic, transcriptional, and posttranscriptional changes in these genes [13,14]
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