Molecular and functional phenotypes of melanoma cells with abnormalities in HLA Class I antigen expression

Abstract

Analysis of melanoma cell lines with abnormalities in HLA Class I antigen expression has identified two serological phenotypes caused by distinct molecular defects. One is characterized by lack of HLA Class I antigen expression which is not induced by IFN-gamma or by incubation at 25 degrees C for 24 hrs. This phenotype reflects structural changes in the beta(2)m gene which interfere with its transcription and/or translation or result in the synthesis of a defective beta(2)-mu polypeptide unable to associate with HLA Class I heavy chains. The other phenotype manifests very low HLA Class I antigen expression which is enhanced by IFN-gamma or by incubation at 25 degrees C for 24 hrs. This phenotype reflects abnormalities in TAP heterodimer expression, which cause defects in stable assembly and intracellular transport of the HLA Class I antigen trimolecular complex. Loss of HLA Class I antigens renders melanoma cells resistant to lysis by HLA Class I antigen-restricted cytotoxic T cells which specifically recognize melanoma associated antigens. Therefore, abnormalities in HLA Class I antigen expression may have a negative impact on the outcome of T cell based immunotherapy. Characterization of the molecular defects underlying loss of HLA Class I antigens may suggest approaches to restore their expression. Inclusion of these approaches in the protocols of T cell based immunotherapy may improve its efficacy.

Cross-Presentation of Tumor Antigens to Effector T Cells Is Sufficient to Mediate Effective Immunotherapy of Established Intracranial Tumors

“…MCA 205 H12 tumor cells are directly recognized by CD8 ϩ T cells derived from tumordraining LN demonstrating that this tumor is fully functional for Ag presentation. 5 In contrast, MCA 205 H12 did not express I-A b , nor was it induced by treatment with 10,000 U/ml IFN-␥ ( (average of 14.5 ϫ 10 6 cells/LN compared with 1.2 ϫ 10 6 per nondraining LN). The tumor-draining LNs contained ϳ40% T lymphocytes, and 14% of the T cells expressed low levels of CD62L (L-selectin) (Fig.…”

“…Defects have been described in several stages of the immune response in the tumor-bearing host including 1) function of APC, 2) T cell signal transduction, 3) production of immunomodulatory products by tumors, and 4) diminished Ag presentation by tumors (1)(2)(3)(4)(5)(6)(7)(8). Because the spontaneous antitumor immune response is usually inadequate, understanding the process through which tumor-reactive T cells are generated and the mechanisms of effector function against tumor cells is important to optimize cancer immunotherapy.…”

Biosynthesis of HLA-C heavy chains in melanoma cells with multiple defects in the expression of HLA-A, -B, -C molecules

“…There is evidence that β 2 m and/or antigenic peptides are available in limiting amounts in a significant percentage of melanoma cells (Wang et al, 1996). The considerable stability of HLA-C polypeptides in β 2 m-defective FO-1 cells suggests that HLA-C may be less affected than HLA-A and -B heavy chains by imbalances in the three subunits of the class I HLA complex.…”

High frequency of allele-specific down-regulation of HLA class I expression in uveal melanoma cell lines

“…One of the underlying causes for limited responses may be the down-regulated surface expression of HLA molecules on the tumor since cytotoxic T lymphocytes need an adequate HLA expression level to recognize and kill tumor cells. Down-regulation of HLA expression has been demonstrated in many different types of cancer, including melanoma (Garrido et al, 1995;Wang et al, 1996).…”

“…One of the underlying causes for limited responses may be the down-regulated surface expression of HLA molecules on the tumor since cytotoxic T lymphocytes need an adequate HLA expression level to recognize and kill tumor cells. Down-regulation of HLA expression has been demonstrated in many different types of cancer, including melanoma (Garrido et al, 1995;Wang et al, 1996).In uveal melanoma, low expression of HLA-A and -B on the primary tumor has been correlated with better patient survival (Blom et al, 1997a), suggesting a protective role for natural killer (NK) cells, which can attack target cells more efficiently in the absence of HLA class I molecules (Storkus et al, 1987;Liao et al, 1991). Furthermore, the HLA class I-positive tumor cells may develop into (micro)metastases.…”