Immune Escape Mechanisms in Retinoblastoma

Abstract

Abstract: : Purpose:Malignant transformation of cells is frequently associated with abnormalities in human leukocyte antigen (HLA) expression. These abnormalities may play a role in the clinical course of the disease, because HLA antigens mediate interactions of tumor cells with cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Since eye is an immune privileged site, tumors must use multiple mechanisms to escape from immune–mediated rejection as in our earlier work, we showed that Fas Receptor was decreased in aggressive retinoblastomas. Therefore we studied the expression of HLA and antigen processing molecules (APM) in retinoblastoma and correlated it with tumor invasion. Methods:HLA class I antigen, beta 2 microglobulin, HLA class II antigens and the APM of the HLA class I pathway comprising proteasomal subunits: LMP 2, MECL–1, transporter associated protein: TAP 1 subunit, chaperone proteins: tapasin and calnexin were studied in 30 archival retinoblastoma. Immunoanalysis was done based on International Histocompatibility Working Group Project Description. Results:HLA class I antigen, beta 2 microglobulin, HLA class II antigen, and APM were positive in 12 tumors with no invasion and decreased in 18 tumors with choroidal and optic nerve invasion. The difference in HLA and APM expression between the 2 groups was statistically significant. (p<0.001) Conclusions:Tumors with invasion have a decreased expression of HLA antigens and APM. APM are necessary for efficient peptide delivery for HLA class I antigen expression. Decreased expression of both HLA class I and II antigens may result in an impaired activation of cytotoxic CD8+ T cells and may facilitate the growth of the tumor cells. Partial HLA loss may be advantageous to the tumor because it potentially allows the tumor cells to escape from CTLs directed against immunodominant epitopes, presented by the lost HLA allele, while maintaining resistance to NK cell lysis. Therefore, in the early stage, tumors manage to survive the immune attack by maneuvering HLA expression levels. This allows tumors just gain time for the accumulation of critical mutations, which will eventually provide them with an uncontrollable invasive potential.

Keywords: oncology • retinoblastoma • immunomodulation/immunoregulation