PMID- 31015344 OWN - NLM STAT- MEDLINE DCOM- 20200922 LR - 20231213 IS - 1557-3265 (Electronic) IS - 1078-0432 (Linking) VI - 25 IP - 14 DP - 2019 Jul 15 TI - High-throughput Screening of Human Tumor Antigen-specific CD4 T Cells, Including Neoantigen-reactive T Cells. PG - 4320-4331 LID - 10.1158/1078-0432.CCR-18-1356 [doi] AB - 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 naive 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. CI - (c)2019 American Association for Cancer Research. FAU - Costa-Nunes, Carla AU - Costa-Nunes C AD - Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. FAU - Cachot, Amelie AU - Cachot A AUID- ORCID: 0000-0002-2565-505X AD - Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland. FAU - Bobisse, Sara AU - Bobisse S AD - Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland. FAU - Arnaud, Marion AU - Arnaud M AD - Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland. FAU - Genolet, Raphael AU - Genolet R AD - Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland. FAU - Baumgaertner, Petra AU - Baumgaertner P AUID- ORCID: 0000-0002-9688-2882 AD - Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. FAU - Speiser, Daniel E AU - Speiser DE AUID- ORCID: 0000-0003-2031-3250 AD - Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. FAU - Sousa Alves, Pedro M AU - Sousa Alves PM AD - GSK, Wavre, Belgium. FAU - Sandoval, Federico AU - Sandoval F AD - GSK, Wavre, Belgium. FAU - Adotevi, Olivier AU - Adotevi O AD - University Bourgogne Franche-Comte, INSERM, EFS BFC, UMR1098, Besancon, France. FAU - Reith, Walter AU - Reith W AD - Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. FAU - Protti, Maria Pia AU - Protti MP AD - Tumor Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy. FAU - Coukos, George AU - Coukos G AD - Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland. FAU - Harari, Alexandre AU - Harari A AD - Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland. FAU - Romero, Pedro AU - Romero P AUID- ORCID: 0000-0002-9688-2882 AD - Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland. Camilla.jandus@chuv.ch pedro.romero@hospvd.ch. FAU - Jandus, Camilla AU - Jandus C AD - Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland. Camilla.jandus@chuv.ch pedro.romero@hospvd.ch. LA - eng SI - ClinicalTrials.gov/NCT00112242 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190423 PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (Antigens, Neoplasm) RN - 0 (Cancer Vaccines) RN - 0 (Peptide Fragments) SB - IM MH - Antigens, Neoplasm/blood/*immunology MH - CD4-Positive T-Lymphocytes/*immunology MH - CD8-Positive T-Lymphocytes/*immunology MH - Cancer Vaccines/*immunology MH - Case-Control Studies MH - High-Throughput Screening Assays MH - Humans MH - Immunotherapy MH - Melanoma/blood/*immunology MH - Peptide Fragments/immunology MH - Skin Neoplasms/blood/*immunology MH - Melanoma, Cutaneous Malignant EDAT- 2019/04/25 06:00 MHDA- 2020/09/23 06:00 CRDT- 2019/04/25 06:00 PHST- 2018/05/01 00:00 [received] PHST- 2018/09/20 00:00 [revised] PHST- 2019/04/17 00:00 [accepted] PHST- 2019/04/25 06:00 [pubmed] PHST- 2020/09/23 06:00 [medline] PHST- 2019/04/25 06:00 [entrez] AID - 1078-0432.CCR-18-1356 [pii] AID - 10.1158/1078-0432.CCR-18-1356 [doi] PST - ppublish SO - Clin Cancer Res. 2019 Jul 15;25(14):4320-4331. doi: 10.1158/1078-0432.CCR-18-1356. Epub 2019 Apr 23.