A wild‐type p53 cytotoxic T cell epitope is presented by mouse hepatocarcinoma cells

Abstract

The possibility to identify epitopes presented by tumor cells to cytotoxic T lymphocytes (CTL) has given rise to new fields in tumor immunology. The tumor suppressor gene product p53 is a good candidate antigen because it is involved in the tumorigenesis of many cancers. It accumulates in an inactivated form due to mutation or formation of heterodimers with an oncogene product. Epitopes from the mutant or wild-type p53 proteins are thought to be presented by tumor cells and to induce a tumor-specific CTL response. To identify such epitopes, mouse wild-type p53 peptides encompassing the H-2 Db anchoring motif were tested for their association with the Db molecule. Positive peptides were assayed for their ability to induce CTL in C57BL/6 mice. CTL specific for one wild-type p53 peptide, p232-240, were isolated and found to lyse hepatocarcinoma cell lines established from mice transgenic for simian virus 40 large T antigen which overexpress p53. These results show that the p232-240 epitope from wild-type p53 is naturally processed and presented in H-2b tumor cells.

An Experimental Vaccine Expressing Wild‐Type p53 Induces Protective Immunity against Glioblastoma Cells with High Levels of Endogenous p53

“…Previous reports have demonstrated an efficacious immune response in mice against wild‐type p53 sequences [9–11, 45–47]. Human p53 epitopes expressed by various tumour cells were shown to be recognized by CTLs obtained from HLA‐A2 transgenic mice [48, 49], and killing of human tumour cells by human p53‐induced CTL clones was also reported [49–52].…”

“…The overexpression of the p53 protein in transformed cells could reveal epitopes that either bind with only low affinity to the restricting molecules or that upon binding to MHC determinants are recognized by T‐cell receptors with such low avidity that T cells fail to detect this complex on cells expressing physiologically low levels of p53. Several p53 peptides were shown previously [10] to bind to MHC class I determinants of the H‐2 b haplotype and one spanning amino acids 158–166 (AIYKKSQHM) was recognized by a T‐cell clone to p53 derived from p53 KO mice [8]. In our model, the Vp53‐wt vaccine induced a CD8 + T‐cell response that contributes to protection against tumour challenge, but the response was below the level needed for its detection by conventional in vitro methods.…”

“…Previous results showed that wild‐type p53‐specific cytotoxic T lymphocytes (CTLs) can discriminate in vivo between p53‐overexpressing tumour cells and normal tissue, without causing symptoms of autoimmune disease [8]. Vaccines based on epitopes of wild‐type p53, shown previously to be efficacious in experimental models [9–12], can potentially be used in larger patient populations as compared with vaccines based on specific p53 mutants.…”

External Beam Radiation of Tumors Alters Phenotype of Tumor Cells to Render Them Susceptible to Vaccine-Mediated T-Cell Killing

“…To evaluate CD8 ϩ T-cell responses, spleens were removed as indicated, dispersed into single-cell suspensions, pooled, and coincubated with the CEA peptide (10 g/ml), the H-2D b -restricted peptide p53 232-240 (2 g/ml, KYMCNSSCM; Refs. 23,27), or the H-2K b -restricted peptide p15E 604 -611 (1 g/ml, KSPW-FTTL, referred as gp70 peptide; Ref. 28) for 7 days.…”

Amino acid modifications in the wild type sequence p53 232–240 overcome the poor immunogenicity of this self tumour epitope

“…Overexpression of p53 has been associated with humoral, cytotoxic and proliferative responses in cancer patients [10][11][12]. Moreover, tumour-reactive cytotoxic responses directed against wild type (WT) and mutated p53 epitopes have been induced in mice and from human peripheral blood mononuclear cells [13][14][15][16]. Considering the highly variable nature of p53 mutations in diverse cancers, it would be easier to design immunotherapy against WT p53 epitopes in order to target a broad range of tumours.…”