T-cell repertoire diversity: friend or foe for protective antitumor response?

Abstract

Profiling the T-Cell Receptor (TCR) repertoire is establishing as a potent approach to investigate autologous and treatment-induced antitumor immune response. 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. 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. 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. 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. Finally, we will examine current improvements in terms of T-cell sequencing, discussing advantages and challenges of current methodologies.

Ovarian cancer is detectable from peripheral blood using machine learning over T-cell receptor repertoires

“…Our findings here support the proposition that tumor-relevant signal is maintained by the immune system and is coded in the T-cell repertoire. The TCR repertoire has demonstrated a capacity for picking up this signal [ 40–42 ]. It seems as if changes made by the tumor lead to a response in the immune system.…”

Aspirin use increases risk of immune-related adverse events in cancer patients treated with immunotherapy: analysis of the FAERS database

“…Some researchers have proposed that activated effector T cells also attack normal non-tumor tissues while increasing their anti-tumor activity (Khan and Gerber 2020; Ronen et al 2022). T-cell receptor (TCR) sequencing studies have provided evidence to support this theory (Sanromán Á et al 2023;Porciello et al 2022). In patients treated with Ipiliumumab, researchers detected greater CD4 and CD8 T cell diversity in irAEs patients compared with those who did not experience signi cant adverse reactions (Oh et al 2017).…”

Exploring the Molecular Tumor Microenvironment and Translational Biomarkers in Brain Metastases of Non-Small-Cell Lung Cancer

“…This transition is mediated by the formation of gap junctions between tumor cells and astrocytes which facilitate the transfer of messenger molecules that induce pro-tumor phenotypes in astrocytes. Additionally, the brain TME is further characterized by reduced T cell infiltration and changed diversity in T cell receptor (TCR) sequences compared to primary tumors, highlighting a state of immunosuppression [20,21]. Other factors that remain poorly understood include the influence of cancer-associated fibroblasts (CAFs) and vascular interactions, specifically vascular co-option, which are thought to be integral to tumor growth within the brain.…”

“…receptor (TCR) sequences compared to primary tumors, highlighting a state of immuno-suppression [20,21]. Other factors that remain poorly understood include the influence of cancer-associated fibroblasts (CAFs) and vascular interactions, specifically vascular cooption, which are thought to be integral to tumor growth within the brain.…”