High-throughput Screening of Human Tumor Antigen–specific CD4 T Cells, including Neoantigen-reactive T Cells

Carla Costa-Nunes, Amelie Cachot, Sara Bobisse, Marion Arnaud, Raphael Genolet, Petra Baumgaertner, Daniel E. Speiser, Pedro M. Sousa Alves, Federico Sandoval, Olivier Adotevi, Walter Reith, Maria Pia Protti, George Coukos, Alexandre Harari, Pedro Romero, Camilla Jandus

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Characterization of tumor antigen–specific CD4 T-cell responses in healthy donors and malignant melanoma patients using an in vitro amplified T-cell library screening procedure. Patients and Methods: A high-throughput, human leukocyte antigen (HLA)-independent approach was used to estimate at unprecedented high sensitivity level precursor frequencies of tumor antigen- and neoantigen-specific CD4 T cells in healthy donors and patients with cancer. Frequency estimation was combined with isolation and functional characterization of identified tumor-reactive CD4 T-cell clones. Results: In healthy donors, we report frequencies of na€ve tumor-associated antigen (TAA)-specific CD4 T cells comparable with those of CD4 T cells specific for infectious agents (Tetanus toxoid). Interestingly, we also identified low, but consistent numbers of memory CD4 T cells specific for several TAAs. In patients with melanoma, low frequencies of circulating TAA-specific CD4 T cells were detected that increased after peptide-based immunotherapy. Such antitumor TAA-specific CD4 T-cell responses were also detectable within the tumor-infiltrated tissues. TAA-specific CD4 T cells in patients displayed a highly polyfunctional state, with partial skewing to Type-2 polarization. Finally, we report the applicability of this approach to the detection and amplification of neoantigen-specific CD4 T cells. Conclusions: This simple, noninvasive, high-throughput screening of tumor- and neoantigen-specific CD4 T cells requires little biologic material, is HLA class II independent and allows the concomitant screening for a large number of tumor antigens of interest, including neoantigens. This approach will facilitate the immunomonitoring of preexisting and therapy-induced CD4 T-cell responses, and accelerate the development of CD4 T-cell–based therapies.

Original languageEnglish
Pages (from-to)4320-4331
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number14
DOIs
Publication statusPublished - Jan 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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