Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Snir T

PROVIDER: S-EPMC9950060 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Snir Tom T Philip Hagit H Gordin Miri M Zilberberg Alona A Efroni Sol S

Scientific data 20230223 1

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 cl ...[more]

PMID: 36823176

Similar Datasets

Project description:BackgroundImmune checkpoint inhibitors provide significant clinical benefit to a subset of patients, but novel prognostic markers are needed to predict which patients will respond. This study was initiated to determine if features of patient T cell repertoires could provide insights into the mechanisms of immunotherapy, while also predicting outcomes.MethodsWe examined T cell receptor (TCR) repertoires in peripheral blood of 25 metastatic pancreatic cancer patients treated with ipilimumab with or without GVAX (a pancreatic cancer vaccine), as well as peripheral blood and tumor biopsies from 32 patients treated with GVAX and mesothelin-expressing Listeria monocytogenes with or without nivolumab. Statistics from these repertoires were then tested for their association with clinical response and treatment group.ResultsWe demonstrate that, first, the majority of patients receiving these treatments experience a net diversification of their peripheral TCR repertoires. Second, patients receiving ipilimumab experienced larger changes in their repertoires, especially in combination with GVAX. Finally, both a low baseline clonality and a high number of expanded clones following treatment were associated with significantly longer survival in patients who received ipilimumab but not in patients receiving nivolumab.ConclusionsWe show that these therapies have measurably different effects on the peripheral repertoire, consistent with their mechanisms of action, and demonstrate the potential for TCR repertoire profiling to serve as a biomarker of clinical response in pancreatic cancer patients receiving immunotherapy. In addition, our results suggest testing sequential administration of anti-CTLA-4 and anti-PD-1 antibodies to achieve optimal therapeutic benefit.Trial registrationSamples used in this study were collected from the NCT00836407 and NCT02243371 clinical trials.FundingResearch supported by a Stand Up To Cancer Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research grant (SU2C-AACR-DT14-14). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (AACR). Additional clinical trial funding was provided by AACR-Pancreatic Cancer Action Network Research Acceleration Network grant (14-90-25-LE), NCI SPORE in GI Cancer (CA062924), Quick-Trials for Novel Cancer Therapies: Exploratory Grants (R21CA126058-01A2), and the US Food and Drug Administration (R01FD004819). Research collaboration and financial support were provided by Adaptive Biotechnologies.

Project description:T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by signals and resources, such as cytokines and space, that act independently of TCR specificity. Although it has been demonstrated that disruption of either of these pathways has a profound effect on T-cell development, we do not yet have an understanding of the dynamical interactions of these pathways in their joint shaping of the T cell repertoire. Complete DiGeorge Anomaly is a developmental abnormality that results in the failure of the thymus to develop, absence of T cells, and profound immune deficiency. After receiving thymic tissue grafts, patients suffering from DiGeorge anomaly develop T cells derived from their own precursors but matured in the donor tissue. We followed three DiGeorge patients after thymus transplantation to utilize the remarkable opportunity these subjects provide to elucidate human T-cell developmental regulation. Our goal is the determination of the respective roles of TCR-specific vs. TCR-nonspecific regulatory signals in the growth of these emerging T-cell populations. During the course of the study, we measured peripheral blood T-cell concentrations, TCRbeta V gene-segment usage and CDR3-length spectratypes over two years or more for each of the subjects. We find, through statistical analysis based on a novel stochastic population-dynamic T-cell model, that the carrying capacity corresponding to TCR-specific resources is approximately 1000-fold larger than that of TCR-nonspecific resources, implying that the size of the peripheral T-cell pool at steady state is determined almost entirely by TCR-nonspecific mechanisms. Nevertheless, the diversity of the TCR repertoire depends crucially on TCR-specific regulation. The estimated strength of this TCR-specific regulation is sufficient to ensure rapid establishment of TCR repertoire diversity in the early phase of T cell population growth, and to maintain TCR repertoire diversity in the face of substantial clonal expansion-induced perturbation from the steady state.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets