A T cell repertoire timestamp is at the core of responsiveness to CTLA-4 blockade

Philip, Hagit; Snir, Tom; Gordin, Miri; Shugay, Mikhail; Zilberberg, Alona; Efroni, Sol

doi:10.1016/j.isci.2021.102100

Cited by 9 publications

(10 citation statements)

References 52 publications

(59 reference statements)

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“…These findings encourage non-invasive and early monitoring of patients receiving ICIs to anticipate clinical response to the treatment. The importance to frame early time points and quantify the dynamics of TCR repertoire during immunotherapy, was also confirmed in a syngeneic mouse model of CRC, where the authors identified a transient and initial increase in clonality in parallel with a decreased diversity which gradually receded [ 102 ]. More recently, Wucherpfennig group published an elegant study where, by designing a powerful experimental set up, the authors temporally characterized the response of T-cell subsets to anti-PD-1 and anti-CTLA-4 treatments, both in the tumor and blood of head and neck cancer patients, in a neoadjuvant setting [ 103 ].…”

Section: Introductionmentioning

confidence: 99%

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

Porciello¹,

Franzese

D’Ambrosio³

et al. 2022

J Exp Clin Cancer Res

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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.

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Section: Introductionmentioning

confidence: 99%

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

Porciello¹,

Franzese

D’Ambrosio³

et al. 2022

J Exp Clin Cancer Res

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“…Additionally, since a phenotypical change, such as reduction in tumor size, can occur some time after the peak of the immunological response, it can be difficult to create a snapshot of the immune state at the most relevant time. Moreover, the high variability in the favorable reaction of cancers to immunotherapy, makes it even challenging for researcher to quantify the true dynamics of the immune response 21 . Animal health and ethics.…”

Section: Data Descriptor Openmentioning

confidence: 99%

The temporal behavior of the murine T cell receptor repertoire following Immunotherapy

et al. 2023

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Immunotherapy is now an essential tool for cancer treatment, and the unique features of an individual’s T cell receptor repertoire are known to play a key role in its effectiveness. The repertoire, famously vast due to a cascade of cellular mechanisms, can be quantified using repertoire sequencing. In this study, we sampled the repertoire over several time points following treatment with anti-CTLA-4, in a syngeniec mouse model for colorectal cancer, generating a longitudinal dataset of T cell clones and their abundance. The dynamics of the repertoire can be observed in response to treatment over a period of four weeks, as clonal expansion of specific clones ascends and descends. The data made available here can be used to determine treatment and predict its effect, while also providing a unique look at the behavior of the immune system over time.

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“…Clustering highly similar TCRβ sequences has been applied to understand how ICT changes TCRβ repertoire structure (the number and size of such clusters) (40,41). TCRβs clusters can be linked to TIL phenotype (42,43), and possibly tumor antigen-specificity.…”

Section: Ict Responders Exhibit Early Clonal Expansion Of Tumor-antig...mentioning

confidence: 99%

Early clonal expansion of tumor-infiltrating lymphocytes predicts response to immune checkpoint therapy

Kidman

Zemek

Principe

et al. 2022

Preprint

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Immune checkpoint therapy (ICT) causes durable tumor responses in a subgroup of patients. Profiling T cell receptor beta (TCRβ) repertoire structure in ICT responders and non-responders provides mechanistic insight into what constitutes an effective anti-tumor response, and could result in the development of predictive biomarkers of response to identify and stratify patients for ICT. To examine how the TCRβ repertoire dynamics contribute to ICT response, we utilized an established murine model that excludes variation in host genetics, environmental factors and tumor mutation burden, limiting variation between animals to naturally diverse TCRβ repertoires. Oligoclonal expansion of TCRβ clonotypes that corresponded with a low TCRβ diversity was observed in responding tumors prior to ICT. We modeled TCRβ cluster dynamics during ICT and found that select clonotypes expanded slower in responders compared to non- responders. Clonally expanded CD8+ tumor infiltrating T cells in non-responders exhibited a T cell exhaustion phenotype. We conclude that an early burst of clonal expansion followed by a contraction during ICT is associated with response.

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A T cell repertoire timestamp is at the core of responsiveness to CTLA-4 blockade

Abstract: Response to ICI is associated with pretreatment TCR repertoire in mice TCR repertoire goes through distinct, ICIdependent changes with time Tumor size and its response to ICI can be tracked by TCR repertoire metrics A single time point is found to be a focal point of the immune response

Cited by 9 publications

References 52 publications

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

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

The temporal behavior of the murine T cell receptor repertoire following Immunotherapy

Early clonal expansion of tumor-infiltrating lymphocytes predicts response to immune checkpoint therapy

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