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Detecting Tumor Specific Antigen-Reactive T cells from Tumor Infiltrating Lymphocytes via Interaction Dependent Fucosyl-biotinylation [RNA-seq]

ABSTRACT: Reactivation and clonal expansion of tumor specific antigen (TSA)-reactive T cells are key to the success of checkpoint blockade and adoptive transfer of tumor-infiltrating lymphocyte (TIL) based therapies. There are no reliable markers to specifically identify the repertoire of TSA-reactive T cells due to their heterogeneous composition. Here we introduce FucoID as a general platform to detect endogenous antigen-specific T cells and study their biology. Through this interaction dependent labeling approach, TSA-reactive T cells can be detected and separated from bystander T cells in primary tumor digests based on their cell-surface enzymatic fucosyl-biotinylation. Compared to bystander TILs, TSA-reactive TILs possess a unique gene features according to RNA-seq.

ORGANISM(S): Mus musculus

PROVIDER: GSE145596 | GEO | 2020/10/22

REPOSITORIES: GEO

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Detecting Tumor Specific Antigen-Reactive T cells from Tumor Infiltrating Lymphocytes via Interaction Dependent Fucosyl-biotinylation [TCR-seq]

Project description:Reactivation and clonal expansion of tumor specific antigen (TSA)-reactive T cells are key to the success of checkpoint blockade and adoptive transfer of tumor-infiltrating lymphocyte (TIL) based therapies. There are no reliable markers to specifically identify the repertoire of TSA-reactive T cells due to their heterogeneous composition. Here we introduce FucoID as a general platform to detect endogenous antigen-specific T cells and study their biology. Through this interaction dependent labeling approach, TSA-reactive T cells can be detected and separated from bystander T cells in primary tumor digests based on their cell-surface enzymatic fucosyl-biotinylation. Compared to bystander TILs, TSA-reactive TILs possess a unique gene features according to RNA-seq.

2020-10-22 | GSE154604 | GEO

Distinct epigenetic features of tumor-reactive CD8+ T cells in colorectal cancer patients revealed by genome-wide DNA methylation analysis

Project description:Tumor-reactive CD8+ tumor infiltrating lymphocytes (TILs) represent a subtype of T cells that could recognize and destroy tumor specifically. Understanding the regulatory mechanism of tumor-reactive CD8+ T cells has important therapeutic implications. Yet the DNA methylation status of this T cell subtype has not been elucidated. In this study, we segregated tumor-reactive and bystander CD8+ TILs, as well as naïve and effector memory CD8+ T cell subtypes as controls from colorectal cancer (CRC) patients, to compare their transcriptome and methylome characteristics. Transcriptome profiling confirmed previous conclusion that tumor-reactive TILs have an exhausted tissue-resident memory signature. Whole-genome methylation profiling identified a distinct methylome pattern of tumor-reactive CD8+ T cells, with tumor-reactive markers (CD39 and CD103) being specifically demethylated. In addition, dynamic changes were observed during the transition of naïve T cells into tumor-reactive CD8+ T cells. Transcription factor (TF) binding motif enrichment analysis identified several immune-related TFs, including three exhaustion-related genes (NR4A1, BATF and EGR2) and VDR, that potentially play important regulatory role in tumor-reactive CD8+ T cells. Our study supports the involvement of DNA methylation in shaping tumor-reactive and bystander CD8+ TILs, and provides a valuable resource for the development of novel DNA methylation markers and future therapeutics.

2019-12-12 | GSE141878 | GEO

Tumor-reactive clonotype dynamics dictate clinical response to TIL therapy in melanoma [TCR-Seq]

Project description:Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is effective in cancer patients, yet the profiles, specificity and dynamics of tumor clonotypes remain opaque. Using single-cell RNA/TCR-sequencing, clonotypes were tracked from baseline tumors to ACT products (ACTP) and post-ACT blood and tumor samples from 13 metastatic melanoma patients (NCT03475134). Furthermore, a predictor of tumor-reactive clonotypes was derived from the transcriptomic profiles of tumor-specific or bystander clones. Patients with clinical responses had tumors enriched in tumor-reactive TILs, preferentially expanding in-vitro to generate larger and more tumoricidal products and preferentially re-infiltrating tumors post-ACT. Conversely, lack of responses was associated with tumors devoid of tumor-reactive clonotypes and with cell products mostly composed of blood-borne clonotypes. The exhaustion state characterizing intratumoral tumor-reactive TILs was attenuated during in-vitro expansion and restored after tumor re-engraftment only in responders. Thus, tumor-reactive clonotypes drive clinical response to TIL therapy, providing insight to select patients or improve TILs’ culture.

2023-08-01 | GSE234352 | GEO

Induction of senescence renders cancer cells highly immunogenic

Project description:Cellular senescence is a stress response that activates innate immunity. However, the interplay between senescent cells and the adaptive immune system remains largely unexplored. Here, we show that senescent cells display enhanced MHC class I (MHC-I) antigen processing and presentation. Immunization of mice with senescent syngeneic fibroblasts generates CD8 T cells reactive against both normal and senescent fibroblasts, some of them targeting senescence-associated MHC-I-peptides. In the context of cancer, we demonstrate that senescent cancer cells trigger strong anti-tumor protection mediated by antigen-presenting cells and CD8 T cells. This response is superior to the protection elicited by cells undergoing immunogenic cell death. Finally, induction of senescence in patient-derived cancer cells exacerbates the activation of autologous tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs) with no effect on non-reactive TILs. Our study indicates that immunization with senescent cancer cells strongly activates anti-tumor immunity, and this can be exploited for cancer therapy.

2022-11-09 | PXD034059 | Pride

Detecting Tumor Specific Antigen-Reactive T cells from Tumor Infiltrating Lymphocytes via Interaction Dependent Fucosyl-biotinylation [RNA-seq]

Project description:Detecting Tumor Specific Antigen-Reactive T cells from Tumor Infiltrating Lymphocytes via Interaction Dependent Fucosyl-biotinylation [RNA-seq]

| PRJNA607697 | ENA

Detecting Tumor Specific Antigen-Reactive T cells from Tumor Infiltrating Lymphocytes via Interaction Dependent Fucosyl-biotinylation [TCR-seq]

Project description:Detecting Tumor Specific Antigen-Reactive T cells from Tumor Infiltrating Lymphocytes via Interaction Dependent Fucosyl-biotinylation [TCR-seq]

| PRJNA646760 | ENA

Detecting Tumor Antigen-Specific T Cells via Interaction-Dependent Fucosyl-Biotinylation

Project description:Detecting Tumor Antigen-Specific T Cells via Interaction-Dependent Fucosyl-Biotinylation

| PRJNA646757 | ENA

Myeloid Niches Sustain Antitumor T Cells and License PD-1 Blockade via CD28 Costimulation

Project description:The local mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TILs) and responsiveness to PD-1 blockade remain partly elucidated. In human ovarian cancer we show that tumor-reactive intraepithelial (ie)CD8+ TILs engaged by antigen are polyfunctional and upregulate PD-1, which restrains their effectiveness. PD-1+ TILs exhibit a continuum of TCR-engaged/exhausted states with variable effector fitness related to CD28 costimulation, which they receive in intraepithelial niches involving myeloid antigen-presenting cells (mAPC). Following PD-1 blockade, activation of TILs requires CD28 costimulation mediated in situ by tumor mAPCs, which is locally enhanced by CTLA-4 blockade. CD40 ligand also amplifies TIL responses in situ, especially in tumors in which mAPCs are not activated. Thus, dysfunctional and exhausted TILs, in a state of TCR engagement but without proper CD28 costimulation by mAPCs in situ, are unlikely to fully benefit from PD-1 blockade.

2021-10-12 | GSE178245 | GEO

Transcriptome-based identification of tumor-reactive and bystander CD8+ T cell receptor clonotypes in human pancreatic cancer

Project description:Pancreatic ductal adenocarcinoma (PDAC) is generally refractory to immune checkpoint blockade, although patients with genetically unstable tumors can show modest therapeutic benefit. We previously demonstrated the presence of tumor-reactive CD8+ T cells in PDAC samples. Here, we charted the tumor-infiltrating T cell repertoire in PDAC by combining single-cell transcriptomics with functional testing of T cell receptors (TCRs) for reactivity against autologous tumor cells. On the basis of a comprehensive dataset including 93 tumor-reactive and 65 bystander TCR clonotypes, we delineated a gene signature that effectively distinguishes between these T cell subsets in PDAC, as well as in other tumor indications. This revealed a high frequency of tumor-reactive TCR clonotypes in three genetically unstable samples. In contrast, the T cell repertoire in six genetically stable PDAC tumors was largely dominated by bystander T cells. Nevertheless, multiple tumor-reactive TCRs were successfully identified in each of these samples, thereby providing a perspective for personalized immunotherapy in this treatment-resistant indication.

2024-01-26 | GSE254250 | GEO

Transcription profiling of mouse CMS4 and CMS4-met cell lines after IFNgamma treatment

Project description:The CMS4 sarcoma, kindly provided by A. DeLeo (University of Pittsburgh, Pittsburgh, PA), is a solid tumor of BALB/c (H-2d) origin, which grows aggressively in naive, syngeneic hosts following a s.c. transplant. Although the parental tumor cell line forms few metastatic foci in the lungs following i.v. administration, a highly metastatic subline, termed CMS4-met, was established from lung digests of those mice as described (Ryan MH, Bristol JA, McDuffie E, Abrams SI. Regression of extensive pulmonary metastases in mice by adoptive transfer of antigen-specific CD8(+) CTL reactive against tumor cells expressing a naturally occurring rejection epitope. J Immunol 2001;167:4286-92).<br>In this experiment we compare gene expression kinetics in the CMS4 and CMS4-met cell lines after IFNgamma treatment. Both cells were treated with IFNgamma for 4 and 24 hours respectively. The untreated and treated cells were then used for total RNA isolation, and microarray experiments.

2005-05-08 | E-MEXP-288 | biostudies-arrayexpress

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