Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA DOI Creative Commons
Smita S. Chandran, Jiaqi Ma, Martin G. Klatt

et al.

Nature Medicine, Journal Year: 2022, Volume and Issue: 28(5), P. 946 - 957

Published: April 28, 2022

Public neoantigens (NeoAgs) represent an elite class of shared cancer-specific epitopes derived from recurrently mutated driver genes. Here we describe a high-throughput platform combining single-cell transcriptomic and T cell receptor (TCR) sequencing to establish whether mutant PIK3CA, among the most frequently genomically altered oncogenes, generates immunogenic public NeoAg. Using this strategy, developed panel TCRs that recognize endogenously processed neopeptide encompassing common PIK3CA hotspot mutation restricted by prevalent human leukocyte antigen (HLA)-A*03:01 allele. Mechanistically, immunogenicity NeoAg arises enhanced neopeptide/HLA complex stability caused preferred HLA anchor substitution. Structural studies indicated HLA-bound presents comparatively 'featureless' surface dominated peptide's backbone. To bind epitope with high specificity affinity, discovered lead TCR clinical candidate engages through extended interface facilitated unusually long CDR3β loop. In patients diverse malignancies, observed clonal conservation spontaneous neoepitope. Finally, adoptive transfer TCR-engineered cells led tumor regression in vivo mice bearing PIK3CA-mutant tumors but not wild-type tumors. Together, these findings therapeutic potential PIK3CA-derived

Language: Английский

Clonal replacement of tumor-specific T cells following PD-1 blockade DOI
Kathryn E. Yost, Ansuman T. Satpathy, Daniel K. Wells

et al.

Nature Medicine, Journal Year: 2019, Volume and Issue: 25(8), P. 1251 - 1259

Published: July 29, 2019

Language: Английский

Citations

1194
Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition) DOI Open Access
Andrea Cossarizza, Hyun‐Dong Chang, Andreas Radbruch

et al.

European Journal of Immunology, Journal Year: 2019, Volume and Issue: 49(10), P. 1457 - 1973

Published: Oct. 1, 2019

These guidelines are a consensus work of considerable number members the immunology and flow cytometry community. They provide theory key practical aspects enabling immunologists to avoid common errors that often undermine immunological data. Notably, there comprehensive sections all major immune cell types with helpful Tables detailing phenotypes in murine human cells. The latest techniques applications also described, featuring examples data can be generated and, importantly, how analysed. Furthermore, tips, tricks pitfalls avoid, written peer-reviewed by leading experts field, making this an essential research companion.

Language: Английский

Citations

881
Neoantigen vaccine: an emerging tumor immunotherapy DOI Creative Commons
Peng Miao,

Yongzhen Mo,

Yian Wang

et al.

Molecular Cancer, Journal Year: 2019, Volume and Issue: 18(1)

Published: Aug. 23, 2019

Genetic instability of tumor cells often leads to the occurrence a large number mutations, and expression non-synonymous mutations can produce tumor-specific antigens called neoantigens. Neoantigens are highly immunogenic as they not expressed in normal tissues. They activate CD4+ CD8+ T generate immune response have potential become new targets immunotherapy. The development bioinformatics technology has accelerated identification combination different algorithms identify predict affinity neoantigens major histocompatibility complexes (MHCs) or immunogenicity is mainly based on whole-exome sequencing technology. Tumor vaccines targeting include nucleic acid, dendritic cell (DC)-based, cell, synthetic long peptide (SLP) vaccines. with checkpoint inhibition therapy radiotherapy chemotherapy might achieve better therapeutic effects. Currently, several clinical trials demonstrated safety efficacy these Further technologies algorithms, well an improvement our understanding mechanisms underlying development, will expand application neoantigen future.

Language: Английский

Citations

567
Peptide-Based Vaccines: Current Progress and Future Challenges DOI Open Access
Ryan J. Malonis, Jonathan R. Lai,

Olivia Vergnolle

et al.

Chemical Reviews, Journal Year: 2019, Volume and Issue: 120(6), P. 3210 - 3229

Published: Dec. 5, 2019

Vaccines have had a profound impact on the management and prevention of infectious disease. In addition, development vaccines against chronic diseases has attracted considerable interest as an approach to prevent, rather than treat, conditions such cancer, Alzheimer's disease, others. Subunit consist nongenetic components agent or disease-related epitope. this Review, we discuss peptide-based their potential in three therapeutic areas: cancer. We factors that contribute vaccine efficacy how these parameters may potentially be modulated by design. examine both clinically tested well nascent approaches explore current challenges remedies. While peptide hold substantial promise human many obstacles remain hampered clinical use; thus, continued research efforts address are warranted.

Language: Английский

Citations

505
Neoantigens: promising targets for cancer therapy DOI Creative Commons
Na Xie, Guobo Shen, Wei Gao

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Jan. 6, 2023

Abstract Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell therapy antibody-based therapies, especially for solid tumors. Neoantigens are newly formed antigens generated by cells as a result various tumor-specific alterations, such genomic mutation, dysregulated RNA splicing, disordered post-translational modification, integrated viral open reading frames. recognized non-self trigger an immune response that is not subject to central peripheral tolerance. The quick identification prediction neoantigens been made possible advanced next-generation sequencing bioinformatic technologies. Compared tumor-associated antigens, highly immunogenic provide emerging targets personalized serve prospective predictors survival prognosis checkpoint blockade responses. therapies will be aided understanding mechanism underlying neoantigen-induced anti-tumor streamlining process neoantigen-based immunotherapies. This review provides overview on characterization outlines clinical applications immunotherapeutic strategies based neoantigens. We also explore their current status, inherent challenges, translation potential.

Language: Английский

Citations

483
Noncoding regions are the main source of targetable tumor-specific antigens DOI Open Access
Céline M. Laumont, Krystel Vincent, Leslie Hesnard

et al.

Science Translational Medicine, Journal Year: 2018, Volume and Issue: 10(470)

Published: Dec. 5, 2018

A proteogenomic method identifies potentially actionable tumor-specific antigens and shows that most of them are not coded by classic exons.

Language: Английский

Citations

453
The Emerging Landscape of Immune Cell Therapies DOI Creative Commons
Evan W. Weber, Marcela V. Maus, Crystal L. Mackall

et al.

Cell, Journal Year: 2020, Volume and Issue: 181(1), P. 46 - 62

Published: April 1, 2020

Language: Английский

Citations

363
Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers DOI
Frank J. Lowery, Sri Krishna,

Rami Yossef

et al.

Science, Journal Year: 2022, Volume and Issue: 375(6583), P. 877 - 884

Published: Feb. 24, 2022

The accurate identification of antitumor T cell receptors (TCRs) represents a major challenge for the engineering cell-based cancer immunotherapies. By mapping 55 neoantigen-specific TCR clonotypes (NeoTCRs) from 10 metastatic human tumors to their single-cell transcriptomes, we identified signatures CD8

Language: Английский

Citations

277
High-throughput targeted long-read single cell sequencing reveals the clonal and transcriptional landscape of lymphocytes DOI Creative Commons
Mandeep Singh, Ghamdan Al‐Eryani, Shaun Carswell

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: July 16, 2019

High-throughput single-cell RNA sequencing is a powerful technique but only generates short reads from one end of cDNA template, limiting the reconstruction highly diverse sequences such as antigen receptors. To overcome this limitation, we combined targeted capture and long-read T-cell-receptor (TCR) B-cell-receptor (BCR) mRNA transcripts with short-read transcriptome profiling barcoded libraries generated by droplet-based partitioning. We show that Repertoire Gene Expression Sequencing (RAGE-Seq) can generate accurate full-length receptor at nucleotide resolution, infer B-cell clonal evolution identify alternatively spliced BCR transcripts. apply RAGE-Seq to 7138 cells sampled primary tumor draining lymph node breast cancer patient track profiles expanded lymphocyte clones across tissues. Our results demonstrate method for tracking large numbers lymphocytes applicable study immunity, autoimmunity cancer.

Language: Английский

Citations

259
Dynamics and specificities of T cells in cancer immunotherapy DOI
Giacomo Oliveira, Catherine J. Wu

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 23(5), P. 295 - 316

Published: April 12, 2023

Language: Английский

Citations

255