![]() ![]() Unravelling the dynamic behavior of the TCR repertoire during ICT will be highly valuable for tracking and understanding anti-tumor immunity, biomarker discovery, and ultimately for the development of novel strategies to improve patient outcomes. The field of immuno-sequencing is rapidly developing and cross-disciplinary efforts are required to maximize the analysis, application, and validation of sequencing data. Single-cell sequencing is a breakthrough technology that can link phenotype with specificity, identifying T cell clones that are crucial for successful ICT. Discovery of predictive biomarkers could lie in novel analysis approaches, such as network analysis of amino acids similarities between TCR sequences. We discuss the advantages and limitations of current metrics used to characterize and represent TCR repertoire diversity. We will also explore how changes to the repertoire in different anatomical locations can better correlate and perhaps predict treatment outcome. Here, we review how the repertoire influences response to ICT and conversely how ICT affects repertoire diversity. T cell receptor (TCR) sequencing allows for sensitive tracking of dynamic changes in antigen-specific T cells at the clonal level, giving unprecedented insight into the mechanisms by which ICT alters T cell responses. T cell repertoires can be comprehensively profiled by high-throughput sequencing at the bulk and single-cell level. ![]() The specificity of adaptive immune cells, such as T and B cells, is determined by antigen-specific receptors. ICT primarily acts at the level of adaptive immunity. Understanding immune mechanisms that underlie responsiveness to ICT will help identify predictive biomarkers of response and develop treatments to convert non-responding patients to responding ones. However, the majority of treated patients do not respond. In particular, immune checkpoint therapy (ICT) leads to durable responses in some patients with some cancers. Immunotherapies have revolutionized cancer treatment. 6School of Medicine, University of Western Australia, Perth, WA, Australia.5Canada’s Michael Smith Genome Sciences Centre, Vancouver, BC, Canada.4Telethon Kids Institute, Perth, WA, Australia.3Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia.2School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.1National Centre for Asbestos Related Diseases, Institute of Respiratory Health, University of Western Australia, Perth, WA, Australia.Nowak 1,6, Willem Joost Lesterhuis 1,2,4, Richard A. Joel Kidman 1,2, Nicola Principe 1,2, Mark Watson 3, Timo Lassmann 4, Robert A. Clonal Diversity of Memory CD8 + T Cell Subsets Might Offer a Dynamic Biomarker of ICT Response.Moving Beyond Diversity: Novel Approaches to Study TCR Repertoires.Improving How TCR Repertoire Data is Represented.Expansion of Intra-Tumoral TCR Clonotypes is a Feature of Response to Anti-PD-1 Therapy.Nuanced Analysis of PD-1 + Blood T Cells Might Offer a Biomarker to Response to PD-1/L1 Blockade.Anti-CTLA-4 Drives Clonal Expansion of Tumor Infiltrating Lymphocytes.Anti-CTLA-4 Monotherapy Remodels the Blood TCR Repertoire.TCR Repertoires Can be Characterized by Different Metrics.Sequencing Technology Is Important for the Characterization of TCR Repertoires.Measurements of Dynamic Change in the Immune System Could Offer a Biomarker of ICT Response.ICT is a Revolutionary Cancer Therapy, but Not All Patients Respond.Jude Children's Research Hospital, United States TABLE OF CONTENTS ![]()
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