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Human CD4 cytotoxic T lymphocytes mediate potent tumor control via tumor cell HLA 2 class II expression in a humanized immune system mouse model

ABSTRACT: Human CD4 cytotoxic T lymphocytes mediate potent tumor control via tumor cell HLA 2 class II expression in a humanized immune system mouse model

PROVIDER: PRJNA924727 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23097800.fastq.gz	Fastqsanger.gz
	SRR23097801.fastq.gz	Fastqsanger.gz
	SRR23097802.fastq.gz	Fastqsanger.gz
	SRR23097803.fastq.gz	Fastqsanger.gz
	SRR23097804.fastq.gz	Fastqsanger.gz

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Human CD4 cytotoxic T lymphocytes mediate potent tumor control via tumor cell HLA 2 class II expression in a humanized immune system mouse model

Project description:Efficacy of immune checkpoint inhibitors in cancer can be limited by dysfunction of CD8 T cells or down-regulation of HLA class I. Tumor control mechanisms independent of the CD8/HLA-I axis would bypass these limitations. CD4 cytotoxic T lymphocytes (CTLs) have been detected in diverse human cancers. However, their independent roles in tumor immunity are underexplored. Here, we report CD4 T cell-dependent spontaneous tumor regression and subsequent memory responses in a humanized immune system (HIS) mouse model. HT-29 tumors, which upregulate HLA class II expression in response to IFN-γ, regressed or were eliminated in a subset of tumor implanted HIS mice. Mice with regressing tumors showed increased cytotoxic CD4 T cells in blood and tumors and enhanced HLA-II expression on tumor cells compared to mice with progressing tumors. The intratumoral CD4 T cell subset associated with tumor regression expressed multiple cytotoxic markers and exhibited clonal expansion. Notably, tumor control was abrogated by depletion of CD4 but not CD8 T cells. CD4 T cells derived from tumor-regressing mice exhibited HLA-II-dependent and tumor cell-specific killing ex vivo. Taken together, our study demonstrates a critical role of human CD4 CTLs in mediating potent tumor control independent of CD8 T cells and provides a novel platform to study human CD4 CTL-mediated anti-tumor immunity.

2023-01-22 | GSE223026 | GEO

Human CD4 cytotoxic T lymphocytes mediate potent tumor control in humanized immune system mice.

Project description:Efficacy of immune checkpoint inhibitors in cancers can be limited by CD8 T cell dysfunction or HLA-I down-regulation. Tumor control mechanisms independent of CD8/HLA-I axis would overcome these limitations. Here, we report potent CD4 T cell-mediated tumor regression and memory responses in humanized immune system (HIS) mice implanted with HT-29 colorectal tumors. The regressing tumors showed increased CD4 cytotoxic T lymphocyte (CTL) infiltration and enhanced tumor HLA-II expression compared to progressing tumors. The intratumoral CD4 T cell subset associated with tumor regression expressed multiple cytotoxic markers and exhibited clonal expansion. Notably, tumor control was abrogated by depletion of CD4 but not CD8 T cells. CD4 T cells derived from tumor-regressing mice exhibited HLA-II-dependent and tumor-specific killing ex vivo. Taken together, our study demonstrates a critical role of human CD4 CTLs in mediating tumor clearance independent of CD8 T cells and provides a platform to study human anti-tumor immunity in vivo.

| S-EPMC10130128 | biostudies-literature

Humanized antibody-drug conjugates for SSTR2-positive tumor treatment

Project description:Somatostatin receptor 2 (SSTR2) is overexpressed in neuroendocrine tumors (NETs) and meningiomas. The objective of this study was to develop an SSTR2-targeted therapy to treat both tumor types. We engineered and humanized an anti-SSTR2 monoclonal antibody (mAb) demonstrating strong cancer cell binding, internalization in cancer cells, and tumor specificity, as evidenced by flow cytometry, confocal microscopy, and live-animal imaging. Antibody-drug conjugates (ADCs) were generated by conjugating the SSTR2 mAb with potent payloads, including monomethyl auristatin F (MMAF) or mertansine (DM1). In vitro assessments revealed high cytotoxicity across diverse NET subtypes and meningioma cell lines. In vivo efficacy was confirmed in two mouse models, i.e. subcutaneous NET xenografts and intracranial meningioma xenografts, where treatment inhibited proliferation, induced apoptosis and cell death, exhibited minimal toxicity, and extended survival. The mechanism of action was further elucidated through bulk RNA sequencing post-treatment. These findings highlight the therapeutic potential of our humanized SSTR2 mAb for targeted payload delivery in NETs and meningiomas.

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Identification and regulation of circulating tumor TCR-matched cytotoxic CD4+ lymphocytes by KLRG1 in bladder cancer

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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LMP-420: a novel purine nucleoside analogue with potent cytotoxic effects for chronic lymphocytic leukemia cells

Project description:[original title] LMP-420: a novel purine nucleoside analogue with potent cytotoxic effects for chronic lymphocytic leukemia cells and minimal toxicity for normal hematopoietic cells. LMP-420 induces cytotoxicity and apoptosis to CLL cells in vitro without any negative effects to normal immune cells. This gene expression experiment compares CLL cells treated with LMP-420 versus media alone to investigate the mechanism of action of LMP-420. CLL cells from 13 patients were treated with LMP-420 or media for 24 hours, then RNA was extracted and assayed on U133Plus2 GeneChips.

2011-02-01 | E-GEOD-20211 | biostudies-arrayexpress

ILC2s directly activate anti-tumor cytotoxic CD8+ T lymphocytes by internalizing, processing, and presenting exogenous antigens

Project description:Type-2 innate-lymphoid cells (ILC2s) associate with both tumor promotion and inhibition. We found that ILC2s may induce anti-tumor immunity by a hitherto-unrealized mechanism: they may internalize, process, and present exogenous tumor antigen on major-histocompatibility-complex class-I (MHCI) molecules with costimulatory molecules to CD8+ T cells. This converts the T cells into cytotoxic-T-lymphocytes (CTLs). Specifically, transferring ILC2s into tumor-bearing mice inhibited tumor growth in a CD8+ T cell-dependent manner. Moreover, co-culturing human or murine CD8+ T cells with ILC2s upregulated T-cell expression of cytotoxic molecules. The resulting CTLs efficiently killed tumor cells in vitro and upon transfer into tumor-bearing mice. ILC2s were found to internalize exogenous antigens via clathrin-dependent endocytosis and to process/present them as efficiently as professional antigen-presenting cells for CD8+ T cells (type-1 conventional dendritic cells). Thus, ILC2s can present antigen to CD8+ T cells and induce their tumor-killing activity. This novel finding has promising implications for anti-tumor strategies.

2024-08-31 | GSE241945 | GEO

Identification of a novel class of cytotoxic granules as origin of supramolecular attack particles in T lymphocytes

Project description:Cytotoxic T lymphocytes (CTL) kill malignant and infected cells via cytotoxic proteins such as granzyme B (GzmB) that are released into the immunological synapse in the form of ~110 nm supramolecular attack particles (SMAPs). However, it is not known where SMAPs are stored in the cell and how they are released. To address this, we utilized knock-in mice to label fusogenic cytotoxic granules with synaptobrevin2-mRFP. We identified two classes of fusion-competent granules, single core granules (SCG) and multi core granules (MCG), with different diameter, morphology, and protein composition. Functional analyses demonstrate that both classes of granules fuse with the plasma membrane at the IS. SCG fusion resulted in rapid dispersal of GzmB. MCG labelled with the SMAP marker thrombospondin-1 and their fusion events resulted in deposition of SMAPs. The CTL attack strategy thus includes SCG fusion to disperse immediately active cytotoxic proteins and parallel MCG fusion to deposit concentrated latent SMAPs onto the target.

2022-04-04 | PXD025055 | Pride

Interrupting the nitrosative stress fuels tumor-specific cytotoxic T lymphocytes in pancreatic cancer

Project description:Interrupting the nitrosative stress fuels tumor-specific cytotoxic T lymphocytes in pancreatic cancer

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Transcriptional Reprogramming of Mature CD4 T helper Cells generates distinct MHC class II restricted Cytotoxic T Lymphocytes

Project description:We show here that the T helper-fate is not fixed and that mature antigen-stimulated CD4 T cells can switch off Thpok expression and reactivate CD8- lineage genes. This unexpected plasticity results in the post-thymic termination of the T helper- program and the functional differentiation of distinct MHC class II restricted CD4 cytotoxic T lymphocytes Small intestine CD4 intraepithelial T lymphocytes from ThPOK-GFP reposter mice were isolated and sorted (FACS Aria) based on ThPOK and CD8aa expression. Cell were isolated either from non-experimental ThPOK-GFP reporter mice (WT) or after transfering CD4 naive T cells from ThPOK-GFP reporter mice to RAG-/-recipient animals (TR) as an experimental colitis model. Experimet was done in duplicate.

2012-12-10 | E-GEOD-42277 | biostudies-arrayexpress

Humanized antibody-drug conjugates for SSTR2-positive tumor treatment

Project description:Humanized antibody-drug conjugates for SSTR2-positive tumor treatment

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