Frontiers in Immunology (Nov 2022)

Identification of HLA class I-restricted immunogenic neoantigens in triple negative breast cancer

  • Belén Aparicio,
  • Belén Aparicio,
  • Belén Aparicio,
  • David Repáraz,
  • David Repáraz,
  • David Repáraz,
  • Marta Ruiz,
  • Marta Ruiz,
  • Marta Ruiz,
  • Diana Llopiz,
  • Diana Llopiz,
  • Diana Llopiz,
  • Leyre Silva,
  • Leyre Silva,
  • Leyre Silva,
  • Enric Vercher,
  • Enric Vercher,
  • Enric Vercher,
  • Patrick Theunissen,
  • Patrick Theunissen,
  • Patrick Theunissen,
  • Ibon Tamayo,
  • Ibon Tamayo,
  • Cristian Smerdou,
  • Cristian Smerdou,
  • Ana Igea,
  • Ana Igea,
  • Marta Santisteban,
  • Marta Santisteban,
  • Cristina Gónzalez-Deza,
  • Juan J. Lasarte,
  • Juan J. Lasarte,
  • Sandra Hervás-Stubbs,
  • Sandra Hervás-Stubbs,
  • Sandra Hervás-Stubbs,
  • Pablo Sarobe,
  • Pablo Sarobe,
  • Pablo Sarobe

DOI
https://doi.org/10.3389/fimmu.2022.985886
Journal volume & issue
Vol. 13

Abstract

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Immune checkpoint inhibitor (ICI)-based immunotherapy in triple negative breast cancer (TNBC) is achieving limited therapeutic results, requiring the development of more potent strategies. Combination of ICI with vaccination strategies would enhance antitumor immunity and response rates to ICI in patients having poorly infiltrated tumors. In heavily mutated tumors, neoantigens (neoAgs) resulting from tumor mutations have induced potent responses when used as vaccines. Thus, our aim was the identification of immunogenic neoAgs suitable as vaccines in TNBC patients. By using whole exome sequencing, RNAseq and HLA binding algorithms of tumor samples from a cohort of eight TNBC patients, we identified a median of 60 mutations/patient, which originated a putative median number of 98 HLA class I-restricted neoAgs. Considering a group of 27 predicted neoAgs presented by HLA-A*02:01 allele in two patients, peptide binding to HLA was experimentally confirmed in 63% of them, whereas 55% were immunogenic in vivo in HLA-A*02:01+ transgenic mice, inducing T-cells against the mutated but not the wild-type peptide sequence. Vaccination with peptide pools or DNA plasmids expressing these neoAgs induced polyepitopic T-cell responses, which recognized neoAg-expressing tumor cells. These results suggest that TNBC tumors harbor neoAgs potentially useful in therapeutic vaccines, opening the way for new combined immunotherapies.

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