# Exploiting TCR Repertoire Analysis to Select Therapeutic TCRs for Cancer Immunotherapy

## TL;DR

This review explores using TCR repertoire analysis to identify and engineer T cells for cancer immunotherapy, focusing on both antigen and TCR-based strategies.

## Contribution

The paper introduces TCR-focused approaches as a complement to antigen-focused methods for selecting therapeutic TCRs.

## Key findings

- TCR repertoire analysis can guide the selection of TCRs for adoptive cell therapy.
- Bioinformatic screening of TCR databases improves TCR selection for therapeutic use.
- In vitro validation can confirm cancer reactivity and exclude healthy cell recognition.

## Abstract

Over the past decade, numerous innovative immunotherapy strategies have transformed the treatment of cancer and improved the survival of patients unresponsive to conventional chemotherapy and radiation therapy. Immune checkpoint inhibition approaches aim to block negative regulatory pathways that limit the function of endogenous T cells, while adoptive cell therapy produces therapeutic T cells with high functionality and defined cancer specificity. While CAR engineering successfully targets cancer surface antigens, TCR engineering enables targeting of the entire cancer proteome, including mutated neo-antigens. To date, TCR engineering strategies have focused on the identification of target cancer antigens recognised by well-characterised therapeutic TCRs. In this review, we explore whether antigen-focused approaches could be complemented by TCR-focused approaches, whereby information of the TCR repertoire of individual patients provides the basis for selecting TCRs to engineer autologous T cells for adoptive cell therapy. We discuss how TCR clonality profiles, distribution in T cell subsets, and bioinformatic screening against continuously improving TCR databases can guide the selection of TCRs for therapeutic application. We further outline in vitro approaches to prioritise TCR candidates to confirm cancer reactivity and exclude recognition of healthy autologous cells, which could provide validation for their therapeutic use even when the target antigen remains unknown.