Identification and regulation of circulating tumor TCR-matched cytotoxic CD4+ lymphocytes by KLRG1 in bladder cancer
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PROVIDER: PRJNA1246607 | ENA |
REPOSITORIES: ENA
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Project description:While cytotoxic CD4+ tumor-infiltrating lymphocytes have anti-cancer activity in patients, whether these can be non-invasively monitored and how these are regulated remains obscure. By matching single cells with T cell receptors (TCR) in tumor and blood of bladder cancer patients, we identified distinct pools of tumor-matching cytotoxic CD4+ T cells in the periphery directly reflecting the predominant antigenic specificities of intratumoral CD4+ TILs. On one hand, the granzyme B (GZMB)-expressing cytotoxic CD4+ subset proliferated in blood in response to PD-1 blockade, but was separately regulated by the killer cell lectin-like receptor G1 (KLRG1) which inhibited their killing by interacting with E-cadherin. Conversely, a clonally related, granzyme K (GZMK)-expressing circulating CD4+ population demonstrated basal proliferation and a memory phenotype that may result from activation of GZMB+ cells, but was not directly mobilized by PD-1 blockade. As KLRG1 marked the majority of circulating tumor TCR-matched cytotoxic CD4+ T cells, this work nominates KLRG1 as a means to isolate them from blood and provide a window into intratumoral CD4+ recognition, as well as a putative regulatory receptor to mobilize the cytolytic GZMB+ subset for therapeutic benefit. Our findings also underscore the ontogenic relationship of GZMB- and GZMK-expressing populations and the distinct cues that regulate their activity.
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Project description:Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer. Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression. One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy. These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality. Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy. Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy.
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Project description:Effector cytotoxic T lymphocytes (CTLs) are critical for ridding the body of infected or cancerous cells. Recognition of an antigenic ligand by the CTL’s T cell receptor (TCR) triggers a signalling cascade that ultimately results in the targeted release of cytolytic granules and/or secretion of cytokines and chemokines to alert and recruit additional immune cells. These signalling cascades are capable of initiating transcription, translation, and cytoskeletal rearrangements. While previous work has demonstrated how translation and intracellular reorganisation contribute to CTL effector responses, the role of transcription is less well studied. To address this, we examined the impact of blocking transcription on the CTL proteome during TCR stimulation. These data demonstrated a strong transcriptional requirement for expression of cytokines and chemokines but not cytolytic molecules. Together with functional studies, these data reveal differential molecular control of the cell-cell communication and cytolytic functions of effector CTLs. CTLs exhibit complete and persistent priming for cytolytic activity prior to target cell encounter, but they require de novo transcription to recruit additional immune cells that amplify the response.
2023-10-16 | PXD034920 | Pride
Project description:We wished to examine early transcriptional changes that occur after TCR engagement in CD8+ cytotoxic T lymphocytes (CTLs). To this end, we differentiated effector CTLs from OTI TCR transgenic mice for 7 days in vitro and then stimulated them with anti-CD3 for various times before lysing for RNA-seq. Results demonstrated significant transcriptional changes starting from 20 minutes. After 60 minutes, upregulated genes were most enriched for cytokines and transcriptional machinery.
2023-10-15 | E-MTAB-12083 | biostudies-arrayexpress
Project description:Mouse small intestine intraepithelial lymphocytes (IEL) that express a ab TCR and CD8aa homodimers are an enigmatic T cell subset, as their specificity and in vivo function remain to be defined. To gain insight into the nature of these cells, we performed global gene expression profiling using microarray analysis, combined with PCR and flow cytometry to determine the level of expression of selected genes. Using these methods, TCR ab+ CD8aa IEL were compared to their TCR ab+ CD8b+ and TCR gd+ counterparts. Experiment Overall Design: In this study, the three IEL populations were isolated by cell sorting from a pool of IELs from 20 mice. RNA from each IEL subset was used to probe one microarray. A replicate experiment was performed on a seperate occasion using a new pool of 20 mice and three additional microarrays were used.
2008-06-13 | E-GEOD-5355 | biostudies-arrayexpress
Project description:The present study reports an unbiased analysis of the cytotoxic T cell serine-threonine phosphoproteome using high resolution mass spectrometry. Approximately 2,000 phosphorylations were identified in CTLs of which approximately 450 were controlled by TCR signaling. A significantly overrepresented group of molecules identified in the phosphoproteomic screen were transcription activators, co-repressors and chromatin regulators. A focus on the chromatin regulators revealed that CTLs have high expression of the histone deacetylase HDAC7 but continually phosphorylate and export this transcriptional repressor from the nucleus. HDAC7 dephosphorylation results in its nuclear accumulation and suppressed expression of genes encoding key cytokines, cytokine receptors and adhesion molecules that determine CTL function. The screening of the CTL phosphoproteome thus reveals intrinsic pathways of serine-threonine phosphorylation that target chromatin regulators in CTLs and determine the CTL functional program. We used Affymetrix microarray analysis to explore the molecular basis for the role of HDAC7 in CTLs and the impact of GFP-HDAC7 phosphorylation deficient mutant expression on the CTL transcriptional profile. In vitro generated P14 TCR cytotoxic T cells were retrovirally infected with a construct encoding GFP-HDAC7 phosphorylation deficient mutant, sorted in base of GFP expression (GFP positive and GFP negative) and processed for microarray analysis in three biological replicas.
2011-03-13 | E-GEOD-27092 | biostudies-arrayexpress
Project description:The goal of this study is to characterize the transcriptional profile of three memory CD8 T cell subsets: IL-7Rα+KLRG1- (memory precursors, MP), IL-7Rα+KLRG1+ (KLRG1+ MP) and IL-7Rα-KLRG1+ (terminal effectors, TE).
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