Molecular T-Cell Repertoire Analysis as Source of Prognostic and Predictive Biomarkers for Checkpoint Blockade Immunotherapy

Abstract

The T cells are key players of the response to checkpoint blockade immunotherapy (CBI) and monitoring the strength and specificity of antitumor T-cell reactivity remains a crucial but elusive component of precision immunotherapy. The entire assembly of T-cell receptor (TCR) sequences accounts for antigen specificity and strength of the T-cell immune response. The TCR repertoire hence represents a "footprint" of the conditions faced by T cells that dynamically evolves according to the challenges that arise for the immune system, such as tumor neo-antigenic load. Hence, TCR repertoire analysis is becoming increasingly important to comprehensively understand the nature of a successful antitumor T-cell response, and to improve the success and safety of current CBI.

Keywords: T-cell repertoire; TCR clonotype; checkpoint blockade immunotherapy.

Figure 1

Interplay between co-stimulatory and inhibitory signals of a T-cell interacting with an antigen presenting cell (APC) or a cancer cell. See text for details.

Figure 2

(a,b) The diversity of T-cell receptor (TCR)αβ is a result of genetic recombination and diversification mechanisms occurring at the α and β TCR chain loci. Diversity is first created in the germline via recombination of variable V, diversity D (for β chain), and joining J segments. Further diversification occurs through imprecise junctions of these gene segments (addition of P- and N-nucleotides adjacent to the D segment), and the combination of α and β chains.

Figure 3

General workflow for TCR repertoire sequencing and analysis. From bulk samples (tissues or peripheral blood) or sorted cells, genomic DNA of mRNA templates are isolated and amplified by polymerase chain reaction (PCR) with specific primers to generate to generate the TCR library. High-throughput sequencing generate the TCR sequencing data that can be analyzed with bioinformatics tools based on different research objectives.