![]() ![]() Repertoire diversity is inversely related to clonality, which refers to the number and frequency of observed TCRs within a sample, and together with diversity is often used as a meter of immune response efficacy (please see Glossary section for definitions and quantification of repertoire diversity measures). The introduction of the latter parameter contributed to the distinction between different clonal compositions, as richness alone does not fully describe cell expansion among the limitedly distributed T-cell populations. The development of major technical and computational advancements allowed to uncover more layers of complexity underlying T-cell diversity, leading to the introduction of two novel concepts: richness, that refers to the number of unique elements in a population, and evenness, referring to the distribution of the frequencies of those elements. Diversity is further reduced by natural selective pressures, and even more so by the aging process, as senescence gradually impairs the potential of naïve T cells to respond to new Ags leading to higher representation of more differentiated effector and/or memory T-cell pools. However, although extraordinary, TCR diversity is limited and constantly shaped by both thymic production and, in the periphery, by homeostatic mechanisms keeping in check cell proliferation and death. Three stages, mostly occurring in the thymus, shape TCR diversity: somatic recombination of variable (V), diversity (D, β chain only), and joining (J) gene segments to generate variable TCR α and β chains, followed by random nucleotide insertion or deletion between the spliced gene V(D)J junctions, and combinatorial pairing which ultimately may lead to a theoretical generation of up to 2 × 10 19 single αβ chain pairs. Effective T-cell responses rely on highly diverse TCR repertoires which ensure the capability to identify a wide range of Ags. Specific TCR-pMHC interaction stimulates thymocyte development into immunocompetent T cells, triggers clonal expansion and differentiation into mature and phenotypically distinct T cells in the periphery, while preserving self-tolerance. Each TCR can recognize short peptides derived from the degradation of self and foreign proteins, presented by major histocompatibility complex (MHC). T cells clonally display on their cell surface an enormous number of different antigen (Ag)-specific TCRs which are multimeric complexes, made of a heterodimer of α and β chains, forming the Ag-binding site (TCR), and the signaling-transducing subunits (CD3). T lymphocytes are the central mediators of the adaptive immune system and play a crucial role in immune surveillance and cancer eradication. The advent of immunotherapy, including vaccines, Immune Checkpoint Inhibitors (ICIs), adoptive T-cell and Chimeric Antigen Receptor-T (CAR-T) cell therapy, buttressed by the development of accurate experimental and computational tools, has revolutionized the field of anti-cancer treatment, thus instigating the need of a deep characterization in terms of T-cell clonality, antitumor functionality and clinical effectiveness of immunotherapy. Finally, we will examine current improvements in terms of T-cell sequencing, discussing advantages and challenges of current methodologies. In particular, we will explore how specific TCR repertoires in cancer patients can be predictive of prognosis or response to therapy and in particular how a given TCR re-arrangement, following immunotherapy, can predict a specific clinical outcome. In this review we will discuss the relationship between global metrics characterizing the TCR repertoire such as T-cell clonality and diversity and the resultant functional responses. A precise spatiotemporal variation of T-cell repertoire, which dynamically mirrors the functional state of the evolving host-cancer interaction, allows the tracking of the T-cell populations at play, and may identify the key cells responsible for tumor eradication, the evaluation of minimal residual disease and the identification of biomarkers of response to immunotherapy. Technical and computational breakthroughs, including high throughput next-generation sequencing (NGS) approaches and spatial transcriptomics, are providing unprecedented insight into the mechanisms underlying antitumor immunity. Profiling the T-Cell Receptor (TCR) repertoire is establishing as a potent approach to investigate autologous and treatment-induced antitumor immune response. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |