Immunological characterization of missense mutations occurring within cytotoxic T cell‐defined p53 epitopes in HLA‐A*0201⁺ squamous cell carcinomas of the head and neck

Abstract

Previous analyses of p53 in 40 HLA-A*0201(HLA-A2) 1 squamous cell carcinomas of the head and neck (SCCHN) indicated that 6/13 p53 missense mutations that were detected, S149C, T150R, V157F, Y220C, Y220H and E271K, occurred within HLA-A2-restricted cytotoxic T lymphocyte (CTL)-defined p53 epitopes. Of the 6, the p53 S149C, Y220C and Y220H peptides were immunogenic. Anti-p53 mutant S149C and Y220H effector cells crossreacted against the parental wild type sequence (wt) p53 peptides, whereas anti-p53 Y220C effector cells were specific for the mutant peptide, p53 Y220C cDNA-transfected HLA-A2 1 SaOS cells, and an HLA-A2 1 SCCHN cell line naturally expressing the mutation. These results indicate that the p53 Y220C mutation can be processed and presented for CD8 1 T cell recognition. Furthermore, using an autologous PBMC/tumor system, anti-p53 Y220C peptide-effector cells recognizing the autologous tumor could also be generated. Our analysis of p53 in 10 additional HLA-A2 1 SCCHN tumors detected the p53 Y220C in 2/10 tumors raising the overall frequency of the p53 Y220C mutation to 6/50 (12%) HLA-A2 1 SCCHN tumors. In contrast, independent of their HLA class I genotypes, the p53 Y220C mutation frequency for all human tumors analyzed to date is 1.5%. This unexpectedly high frequency of the p53 Y220C mutation in HLA-A2 1 SCCHN suggests that vaccines targeting this mutation would not only be expected to induce robust anti-tumor immune responses in HLA-A2 1 subjects, but also be more widely applicable than previously envisioned for any given p53 missense mutation. ' 2007 Wiley-Liss, Inc.

A catalog of HLA type, HLA expression, and neo-epitope candidates in human cancer cell lines

“…The TP53 missense mutation Y220C produces an immunogenic neo-epitope (VVPCEPPEV) in HLA-A*02:01 positive squamous cell carcinomas of the head and neck. 26 This mutation is also present in the breast cancer cell line HCC-1419 (Cosmic and CCLE) and we predict the same mutation-producing peptide to bind to HLA-A*02:01 with high affinity (399.95 nM; Table S3). …”

Opportunities and challenges for TCR mimic antibodies in cancer therapy

“…[25] Research groups designing TCRm antibodies should focus on identifying recurrent neoantigens (such as those found in KRAS G12V/C, p53,[26] or BCR-ABL). [27,28] Despite the low likelihood of a tumor having any given neoantigen, a sufficiently large population may benefit from the development of high-quality TCRm to neoantigens with as little as 1% tumor prevalence.…”

Modulation of immune responses by the tumor suppressor p53

“…First identified in the sera of cancer patients more than 30 years ago [103,104], the appearance of circulating antibodies against p53 has led to an alternative p53 antigen approach to cancer therapy. In addition to alteration of the p53 regulatory network in most human cancers, the overexpression of mutated p53 protein in several human tumors [105] suggests it could be a potential antigen in cancer immunotherapy since mutated p53 has features of non-self antigen [106]. One strategy is based on the observation that most p53 mutants are due to single amino acid changes that extend protein half-life, leading to accumulation in tumor cells [105,107,108].…”