Immune selective pressure and HLA class I antigen defects in malignant lesions

Abstract

The revived cancer immune surveillance theory has emphasized the active role the immune system plays in eliminating tumor cells and in facilitating the emergence of their immunoresistant variants. MHC class I molecule abnormalities represent, at least in part, the molecular phenotype of these escape variants, given the crucial role of MHC class I molecules in eliciting tumor antigen-specific T cell responses, the high frequency of HLA class I antigen abnormalities in malignant lesions and their association with a poor clinical course of the disease. Here, we present evidence for this possibility and review the potential mechanisms by which T cell selective pressure participates in the generation of tumor cells with MHC class I molecule defects. Furthermore, we discuss the strategies to counteract tumor cell immune evasion.

Fig. 1

Host immune system’s adaptation to tumor immune escape and multiple HLA class I antigen defects. When a tumor cell carrying a HLA-A2, -A3, -B5, -B7 phenotype is exposed to immune selective pressure imposed by HLA-A3-restricted, TA-specific CTLs, its variants harboring a single defect in the expression of the immunodominant HLA-A3-TA peptide complexes will not be destroyed and survive. These single defects, as illustrated here, may include a selective HLA-A3 allospecificity loss, which abolishes HLA-A3-TA peptide complex expression, b APM component downregulation, which causes a general change in the presented TA peptide repertoire, c TAP1 loss, which reduces the amount of presented TA peptides on all allospecificities except HLA-A2, which can present TAP-independent peptides, and d immunoproteasome component (LMP2, LMP7 and LMP10) expression, which changes the type of peptides processed and presented on certain allospecificities. In response to these single HLA class I antigen defects, the host immune specificity changes and then targets the second immunodominant CTL epitopes, namely the HLA-A2–TA peptide complexes. When exposed to selective pressure imposed by HLA-A2-restricted, TA-specific CTLs, the tumor variants that harbor an additional defect in HLA-A2–TA peptide complex expression will emerge and become the predominant populations. The second defects added to the previous ones may include a′ and b′ HLA-A2 allospecificity loss, which abolishes HLA-A2–TA peptide complex expression, c′ β₂m loss, which results in total HLA class I antigen loss, and d′ APM component downregulation, which changes the peptide repertoire previously processed by the immunoproteasome