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Defective major histocompatibility complex class I expression in a sarcomatoid renal cell carcinoma cell line
M K Jakobsen1, N P Restifo, P A Cohen
1Surgery Branch, National Cancer Institute, Bethesda, Maryland, USA.
Insights
Renal cell carcinoma (RCC) cells lacking beta 2-microglobulin (beta 2m) fail to express MHC class I. This defect prevents antigen presentation, allowing tumors to evade immune detection.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Major histocompatibility complex (MHC) class I molecules are crucial for immune surveillance.
- Metastatic renal cell carcinoma (RCC) can exhibit defects in immune recognition.
- Beta 2-microglobulin (beta 2m) is essential for the proper folding and surface expression of MHC class I.
Purpose of the Study:
- To investigate the expression of MHC class I and beta 2m in renal cell carcinoma (RCC) cell lines.
- To determine the molecular basis for the lack of MHC class I expression in a specific RCC cell line (UOK 123).
- To understand the implications of impaired MHC class I expression for immune evasion in RCC.
Main Methods:
- Analysis of MHC class I and beta 2m surface expression using flow cytometry in 12 RCC cell lines.
- Immunofluorescence staining to detect beta 2m and MHC class I localization within UOK 123 cells.
- Recombinant vaccinia virus-mediated gene transfer to assess the effect of beta 2m re-expression on MHC class I presentation.
Main Results:
- One RCC cell line (UOK 123) exhibited a complete absence of surface beta 2m and MHC class I expression.
- Immunofluorescence revealed no detectable beta 2m in UOK 123 cells, with accumulation of unfolded MHC class I in the endoplasmic reticulum.
- Re-introduction of beta 2m into UOK 123 cells restored normal surface expression of both beta 2m and MHC class I.
Conclusions:
- The lack of beta 2m in UOK 123 cells prevents proper folding and cell surface presentation of MHC class I molecules.
- This defect in MHC class I assembly and expression renders RCC cells unable to present antigens to cytotoxic T cells.
- Impaired MHC class I expression represents a mechanism by which renal cell carcinoma can escape immune surveillance.
Abstract:
We studied major histocompatibility complex (MHC) class I expression in 12 tumor cell culture lines established from patients with metastatic renal cell carcinoma (RCC). In one of these cell culture lines, UOK 123, we found no surface expression of beta 2-microglobulin (beta 2m) and MHC class I by flow cytometry. Immunofluorescence staining using three different monoclonal antibodies to beta 2m revealed no detectable beta 2m in the endoplasmic reticulum (ER), Golgi apparatus, cytoplasm, or on the cell surface. There was no evidence of folded class I molecules inside or on the surface of the cells; however, the ER stained intensively for unfolded class I molecules. Transient expression of beta 2m by UOK 123 after infection with a recombinant vaccinia virus containing the gene for beta 2m resulted in normal expression of both beta 2m and class I (HLA-A, B, C) determinants assessed by flow cytometry analysis. No expression of class I or beta 2m was seen with the recombinant vaccinia vector carrying a control gene. The inability of class I molecules to reach the cell surface is due to the requirement of beta 2m for proper folding and presentation of the class I MHC complex. The failure to assemble and express MHC class I complex on the cell surface renders these cells incapable of antigen presentation to cytotoxic T cells and provides a mechanism for escape from immune recognition by the tumor.
