Original ArticlesThe HLA crossroad in tumor immunology☆
Introduction
The discovery of the major histocompatibility complex (MHC) and of the laws that govern tissue transplantation was possible in the early days due to the transplantation of tumor cell lines in allogeneic inbred strains of mice 1, 2. For decades, however, a solid scientific basis for tumor immunology was lacking since the nature of tumor antigens was unknown [3]. Elucidation of the crucial role of human leukocyte antigen (HLA) molecules in antigen presentation contributed to the discovery of tumor antigens recognized by T lymphocytes 4, 5. In addition, the description of several different routes used by tumor cells to escape immunosurveillance highlighted the importance of the immune system in controlling tumor growth [6]. Among these routes, the selection of MHC class I-deficient variants is a frequently observed mechanism in experimental and spontaneous tumors 7, 8.
It has been known since the mid 1970’s that MHC class I alterations occur in mouse and human tumors 9, 10, 11. Early reports indicated that private and public H-2 specificities of virally and chemically induced mouse tumors were absent compared with H-2 typing obtained in normal spleen or lymph node cells 12, 13. However, it was not realized until the mid 1980’s that these altered phenotypes could represent a major mechanism of tumor escape from T-cell immune responses 14, 15. More recently, the importance of these findings has been emphasized by the discovery that the immune system has evolved a particular population of cells capable of recognizing and destroying MHC class I-deficient cells produced during viral infection or tumor development, i.e., the natural killer (NK) cells [16]. After 40 years of continuous research and progress in our understanding of how the immune system controls the development and dissemination of experimental and human tumors, it is clear that HLA class I molecules are emerging as leading players in this tumor-host scenario.
This review will focus on the different altered HLA class I phenotypes found in solid human tumors and cell lines, including the mechanisms that generate each of these phenotypes; and the clinical applications of these findings in cancer patients undergoing immunotherapy with peptides.
Section snippets
Altered MHC class I phenotypes in tumors
The use of monoclonal antibodies (mAbs) against HLA class I monomorphic, locus-specific, and allelic-specific determinants with analysis by immunohistological techniques has made it possible to define precisely in cryopreserved tissue sections different altered HLA phenotypes. These alterations seem to occur at a particular step in tumor development: when the tumor invades the surrounding tissues and starts to metastasize [7]. Sometimes results are difficult to interpret because of the
Conclusions
How can our knowledge in HLA and tumor antigens be applied to cancer patients in clinical HLA laboratories? The identification of HLA class I alteration in tumors with the precise definition of the mechanism responsible for them are, doubtless, powerful data to consider when designing a particular vaccination strategy based on HLA mediated T-cell immunotherapy. Indeed, regressions of some melanoma lesions were reported when patients were immunized with peptides encoded by different cellular
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This study was supported by the Fondo de Investigaciones Sanitarias (F.I.S.), el Plan Andaluz e Investigacı́on (P.A.I.) and el Servicio Andaluz de Salud (S.A.S.), Spain.