PMID- 34335558 OWN - NLM STAT- MEDLINE DCOM- 20211026 LR - 20211026 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 12 DP - 2021 TI - Targeting Neoepitopes to Treat Solid Malignancies: Immunosurgery. PG - 592031 LID - 10.3389/fimmu.2021.592031 [doi] LID - 592031 AB - Successful outcome of immune checkpoint blockade in patients with solid cancers is in part associated with a high tumor mutational burden (TMB) and the recognition of private neoantigens by T-cells. The quality and quantity of target recognition is determined by the repertoire of 'neoepitope'-specific T-cell receptors (TCRs) in tumor-infiltrating lymphocytes (TIL), or peripheral T-cells. Interferon gamma (IFN-gamma), produced by T-cells and other immune cells, is essential for controlling proliferation of transformed cells, induction of apoptosis and enhancing human leukocyte antigen (HLA) expression, thereby increasing immunogenicity of cancer cells. TCR alphabeta-dependent therapies should account for tumor heterogeneity and availability of the TCR repertoire capable of reacting to neoepitopes and functional HLA pathways. Immunogenic epitopes in the tumor-stroma may also be targeted to achieve tumor-containment by changing the immune-contexture in the tumor microenvironment (TME). Non protein-coding regions of the tumor-cell genome may also contain many aberrantly expressed, non-mutated tumor-associated antigens (TAAs) capable of eliciting productive anti-tumor immune responses. Whole-exome sequencing (WES) and/or RNA sequencing (RNA-Seq) of cancer tissue, combined with several layers of bioinformatic analysis is commonly used to predict possible neoepitopes present in clinical samples. At the ImmunoSurgery Unit of the Champalimaud Centre for the Unknown (CCU), a pipeline combining several tools is used for predicting private mutations from WES and RNA-Seq data followed by the construction of synthetic peptides tailored for immunological response assessment reflecting the patient's tumor mutations, guided by MHC typing. Subsequent immunoassays allow the detection of differential IFN-gamma production patterns associated with (intra-tumoral) spatiotemporal differences in TIL or peripheral T-cells versus TIL. These bioinformatics tools, in addition to histopathological assessment, immunological readouts from functional bioassays and deep T-cell 'adaptome' analyses, are expected to advance discovery and development of next-generation personalized precision medicine strategies to improve clinical outcomes in cancer in the context of i) anti-tumor vaccination strategies, ii) gauging mutation-reactive T-cell responses in biological therapies and iii) expansion of tumor-reactive T-cells for the cellular treatment of patients with cancer. CI - Copyright (c) 2021 de Sousa, Lerias, Beltran, Paraschoudi, Condeco, Kamiki, Antonio, Figueiredo, Carvalho, Castillo-Martin, Wang, Ligeiro, Rao and Maeurer. FAU - de Sousa, Eric AU - de Sousa E AD - ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal. FAU - Lerias, Joana R AU - Lerias JR AD - ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal. FAU - Beltran, Antonio AU - Beltran A AD - Department of Pathology, Champalimaud Clinical Centre, Lisbon, Portugal. FAU - Paraschoudi, Georgia AU - Paraschoudi G AD - ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal. FAU - Condeco, Carolina AU - Condeco C AD - ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal. FAU - Kamiki, Jessica AU - Kamiki J AD - ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal. FAU - Antonio, Patricia Alexandra AU - Antonio PA AD - ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal. FAU - Figueiredo, Nuno AU - Figueiredo N AD - Digestive Unit, Champalimaud Clinical Centre, Lisbon, Portugal. FAU - Carvalho, Carlos AU - Carvalho C AD - Digestive Unit, Champalimaud Clinical Centre, Lisbon, Portugal. FAU - Castillo-Martin, Mireia AU - Castillo-Martin M AD - Department of Pathology, Champalimaud Clinical Centre, Lisbon, Portugal. FAU - Wang, Zhe AU - Wang Z AD - Jiangsu Industrial Technology Research Institute (JITRI), Applied Adaptome Immunology Institute, Nanjing, China. FAU - Ligeiro, Dario AU - Ligeiro D AD - Lisbon Centre for Blood and Transplantation, Instituto Portugues do Sangue e Transplantacao (IPST), Lisbon, Portugal. FAU - Rao, Martin AU - Rao M AD - ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal. FAU - Maeurer, Markus AU - Maeurer M AD - ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal. AD - I Medical Clinic, Johannes Gutenberg University of Mainz, Mainz, Germany. LA - eng PT - Journal Article PT - Review DEP - 20210715 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Antigens, Neoplasm) RN - 0 (Cancer Vaccines) RN - 0 (Epitopes, T-Lymphocyte) SB - IM MH - Animals MH - Antigens, Neoplasm/*immunology MH - Cancer Vaccines/*immunology MH - Computational Biology MH - Epitopes, T-Lymphocyte/*immunology MH - Humans MH - Immunotherapy/*methods MH - Lymphocytes, Tumor-Infiltrating/*immunology MH - Neoplasms/*immunology/therapy MH - Precision Medicine MH - T-Lymphocytes/*immunology/transplantation MH - Whole Genome Sequencing PMC - PMC8320363 OTO - NOTNLM OT - T-cell receptor OT - T-cells OT - TIL OT - antigens OT - immunotherapy OT - neoepitopes OT - precision medicine OT - vaccination COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/08/03 06:00 MHDA- 2021/10/27 06:00 PMCR- 2021/01/01 CRDT- 2021/08/02 05:55 PHST- 2020/08/06 00:00 [received] PHST- 2021/05/07 00:00 [accepted] PHST- 2021/08/02 05:55 [entrez] PHST- 2021/08/03 06:00 [pubmed] PHST- 2021/10/27 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2021.592031 [doi] PST - epublish SO - Front Immunol. 2021 Jul 15;12:592031. doi: 10.3389/fimmu.2021.592031. eCollection 2021.