T-cell Responses to TP53 "Hotspot" Mutations and Unique Neoantigens Expressed by Human Ovarian Cancers

Clin Cancer Res. 2018 Nov 15;24(22):5562-5573. doi: 10.1158/1078-0432.CCR-18-0573. Epub 2018 May 31.

Abstract

Purpose: This was a study prospectively evaluating intratumoral T-cell responses to autologous somatic mutated neoepitopes expressed by human metastatic ovarian cancers.Patients and Methods: Tumor-infiltrating lymphocytes (TIL) were expanded from resected ovarian cancer metastases, which were analyzed by whole-exome and transcriptome sequencing to identify autologous somatic mutations. All mutated neoepitopes, independent of prediction algorithms, were expressed in autologous antigen-presenting cells and then cocultured with TIL fragment cultures. Secretion of IFNγ or upregulation of 41BB indicated a T-cell response.Results: Seven women with metastatic ovarian cancer were evaluated, and 5 patients had clear, dominant T-cell responses to mutated neoantigens, which were corroborated by comparison with the wild-type sequence, identification of the minimal epitope, human leukocyte antigen (HLA) restriction element(s), and neoantigen-specific T-cell receptor(s). Mutated neoantigens were restricted by HLA-B, -C, -DP, -DQ, and/or -DR alleles and appeared to principally arise from random, somatic mutations unique to each patient. We established that TP53 "hotspot" mutations (c.659A>G; p.Y220C and c.733G>A; p.G245S) expressed by two different patients' tumors were both immunogenic in the context of HLA-DRB3*02:02.Conclusions: Mutation-reactive T cells infiltrated ovarian cancer metastases at sufficient frequencies to warrant their investigation as adoptive cell therapy. In addition, transfer of TP53 "hotspot" mutation-reactive T-cell receptors into peripheral blood T cells could be evaluated as a gene therapy for a diverse range of tumor histologies. Clin Cancer Res; 24(22); 5562-73. ©2018 AACR See related commentary by McNeish, p. 5493.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Sequence
  • Antigens, Neoplasm / immunology*
  • Cell Line, Tumor
  • Epitope Mapping
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • HLA Antigens / immunology
  • Histones / genetics
  • Histones / immunology
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Mutation*
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / immunology*
  • Ovarian Neoplasms / pathology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / immunology*
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / immunology

Substances

  • Antigens, Neoplasm
  • Epitopes, T-Lymphocyte
  • HLA Antigens
  • Histones
  • Receptors, Antigen, T-Cell
  • Tumor Suppressor Protein p53
  • USP9X protein, human
  • Ubiquitin Thiolesterase