Overexpressed oncogenic tumor-self antigens

Abstract

Overexpressed tumor-self antigens represent the largest group of candidate vaccine targets. Those exhibiting a role in oncogenesis may be some of the least studied but perhaps most promising. This review considers this subset of self antigens by highlighting vaccine efforts for some of the better known members and focusing on TPD52, a new promising vaccine target. We shed light on the importance of both preclinical and clinical vaccine studies demonstrating that tolerance and autoimmunity (presumed to preclude this class of antigens from vaccine development) can be overcome and do not present the obstacle that might have been expected. The potential of this class of antigens for broad application is considered, possibly in the context of low tumor burden or adjuvant therapy, as is the need to understand mechanisms of tolerance that are relatively understudied.

Keywords: ALK, Anaplastic lymphoma kinase; AR, androgen receptor; CTL, cytotoxic T lymphocyte; CTLA-4, cytotoxic T lymphocyte-associated antigen 4; HLA, human leukocyte antigen; Her-2/neu, human epithelial growth factor receptor 2; ODN, oligodeoxynucleotide; Overexpressed tumor-self antigen; TAA, tumor associated antigen; TPD52; TRAMP, Transgenic adenocarcinoma of the mouse prostate; Treg, T regulatory cell; VEGFR2, vascular endothelial growth factor receptor 2; WT-1, Wilms tumor-1; hD52; hD52, human TPD52; mD52; mD52, murine TPD52; oncogenic; shared; tumor protein D52; universal; vaccine.

Figure 1.

Immunologic character of tumor antigens. Simplified tumor antigen classification based on the immunologic character of the tumor antigen relative to its potential immunogenicity. Depicted are two main classes of antigens represented by tumor-specific and -associated antigens defined by normal cell expression, and four sub-classes ranging from stronger to weaker immunity. Non-self (e.g., viral proteins) and altered-self (e.g., mutant protein or restricted expression) antigens are proposed to elicit strong immune responses, and self antigens, whether involved in oncogenesis (tumor-dependent) or not (tumor-independent), would elicit weaker immune responses.

Figure 2.

Generation of CTLs from normal PBLs with D52 peptide. The data show hD52-specific HLA-A2-restricted killing of human prostate cell lines. hD52 expression in the human prostate cell lines was determined by 30 cycle RT-PCR using hD52-specific primers and GAPDH as an internal reference. (A) Human normal prostate cell line 568 NPTX and tumor cell line LnCap are hD52-low expressors. (B) Killing of human prostate cancer cell lines determined using a standard lysis assay at an E:T of 5:1. Targets: human prostate cancer and normal-derived cells from HLA-A2+ patient 568 (normal = NPTX, tumor = CP1TX and CP2TX) were generated as previously described, human prostate cancer cell lines PC-3 (HLA-A2-) and LnCap (HLA-A2+) are commercially available. Methods: The method used to generate hD52 peptide-specific CTLs by IVS with hD52 peptide Q(A/L)FSHSFS(I/V) has been previously explained in detail.