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

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

PROVIDER: PRJNA738136 | ENA |

REPOSITORIES: ENA

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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

Interactomics of the RLTPR protein explain its essential role for costimulation via CD28

Project description:The RLTPR cytosolic protein has an essential role in CD28 costimulation but its mode of action and importance in human T cells remain elusive. Here, using mass spectrometry we showed that CD28, RLTPR and the CARMA1 cytosolic adaptor physically associate in mouse T cells. Although RLTPR is thought to function as an actin-uncapping protein, this property was dispensable for CD28 costimulation. Our findings underpin the convergent function of RLTPR in T cells and suggest that its scaffolding role predominates during CD28 costimulation.

2016-09-27 | PXD003870 | Pride

Analysis of Th17 gene signature in the presence of CD28 costimulation in human CD4 naïve T cells

Project description:We determined differentially regulated gene expression profile in CD4 naïve T cells cultured in presence or absence of Th17 inducing cytokines (IL23+IL1β) and anti-CD28. We reported that CD28 costimulation induced Th17-suppressive gene signature.

2018-03-12 | GSE110097 | GEO

c-Kit signaling potentiates CAR T-cell efficacy in solid tumors by CD28- and IL-2–independent costimulation

Project description:The limited efficacy of chimeric antigen receptor (CAR) T-cell therapy for solid tumors necessitates engineering strategies that promote functional persistence in an immunosuppressive environment. Herein, we exploit c-Kit signaling, a physiological pathway associated with stemness in hematopoietic progenitor cells (T cells lose expression of c-Kit during differentiation). CAR T cells with intracellular expression—but no cell-surface receptor expression—of the c-Kit D816V mutation (KITv) have upregulated STAT phosphorylation, antigen-activation-dependent proliferation, CD28- and IL-2–independent and IFN-γ–mediated costimulation, augmenting the cytotoxicity of first-generation CAR T cells. This translates to enhanced survival, including in TGF-β–rich and low-antigen-expressing solid tumor models. KITv CAR T cells have equivalent or better in vivo efficacy than second-generation CAR T cells and are susceptible to tyrosine kinase inhibitors (safety switch). When combined with CD28 costimulation, KITv costimulation functions as a third signal, enhancing efficacy and providing a potent approach to treat solid tumors.

2023-04-24 | GSE229026 | GEO

Effect of costimulation on microRNAs levels in human naïve CD4 T cells

Project description:microRNA transcriptional profiling of human naïve CD4 T cells comparing cells that saw no activation, only anti-CD3 or anti-CD3 and anti-CD28 to identify microRNAs specifically upregulated by CD28-mediated costimulation. Three conditions experiment. PBS, anti-CD3, anti-CD3 + anti-CD28 all compared to a reference sample. Biological triplicates, independently extracted and activated.

2012-02-25 | E-GEOD-36071 | biostudies-arrayexpress

CD28-CBCA driven PKM splicing licenses CD8 T cell glycolysis and effector function

Project description:T cells stimulated in the absence of CD28 costimulation are functionally anergic, characterized by reduced glucose metabolism and ability to produce effector cytokines. Surprisingly, previous studies have shown relatively few CD28-specific changes in gene transcription upon costimulation. Using mice expressing mutations in the CD28 cytoplasmic tail, we show a major effect of CD28 costimulation is alternative splicing of numerous genes including the glycolytic enzyme pyruvate kinase (Pkm), which is preferentially spliced from Pkm1 to Pkm2 upon stimulation. PKM2 is dispensable for T cell activation, but necessary for CD8+ T cells to utilize aerobic glycolysis, produce effector cytokines, and provide anti-tumor immunity. Mechanistically, CD28 regulates expression of the Cap-Binding Complex adaptor protein ARS2, which binds Pkm splicing factors and facilitates their interaction with the elongating transcript. Data suggest a major function of CD28 costimulation is control of RNA biogenesis in support of T cell transcriptome remodeling and acquisition of effector function.

2023-09-01 | GSE168824 | GEO

Response of expanded human conventional and regulatory T cells to CD28 or TNFR2 costimulation [Exp2]

Project description:Immune responses depend on a dynamic balance between the opposing activities of conventional (Tconv) and regulatory (Treg) CD4+ T cells. While receptor-targeted approaches have been developed based on their modulation of Tconv cells, Tconv and Treg cells share many costimulatory receptors. We aim to determine key differential signaling events downstream of costimulation to find opportunities for selective manipulation of Tconv or Treg cells. This data set includes the transcriptomes of expanded human Tconv and Treg cells that were treated with anti-CD3, anti-CD3/CD28 or anti-CD3/TNFR2 agonistic mAbs for 24 hours.

2020-07-10 | GSE138604 | GEO

Effect of costimulation on microRNAs levels in human naïve CD4 T cells

2012-02-25 | GSE36071 | GEO

Treg cells from human blood differentiate into non-lymphoid tissue-resident effector cells upon TNFR2 costimulation

Project description:Regulatory T (Treg) cells can facilitate transplant tolerance and attenuate autoimmune- and inflammatory diseases. Therefore, it is clinically relevant to stimulate Treg cell expansion and function in vivo and to create therapeutic Treg cell products in vitro. We report that TNF receptor 2 (TNFR2) is a unique costimulus for naïve, thymus-derived (t)Treg cells from human blood that promotes their differentiation into non-lymphoid tissue (NLT)-resident effector Treg cells, without Th-like polarization. In contrast, CD28 costimulation maintains a lymphoid tissue (LT)-resident Treg cell phenotype. We base this conclusion on transcriptome and proteome analysis of TNFR2- and CD28-costimulated CD4+ Treg cells and conventional T (Tconv) cells, followed by bioinformatic comparison with published transcriptomic Treg cell signatures from NLT and LT in health and disease, including autoimmunity and cancer. These analyses illuminate that TNFR2 costimulation promotes Treg cell capacity for survival, migration, immunosuppression and tissue regeneration. Functional studies confirmed improved migratory ability of TNFR2-costimulated tTreg cells. Flow cytometry validated the presence of the TNFR2-driven Treg cell signature in effector/memory Treg cells from the human placenta as opposed to blood. Thus, TNFR2 can be exploited as driver of NLT-resident Treg cell differentiation for adoptive cell therapy or antibody-based immunomodulation in human disease.

2024-01-24 | PXD048248 | Pride

Response of expanded human conventional and regulatory T cells to CD3/CD28-mediated activation (Exp1) and to CD28 or TNFR2 costimulation (Exp2)

Project description:Response of expanded human conventional and regulatory T cells to CD3/CD28-mediated activation (Exp1) and to CD28 or TNFR2 costimulation (Exp2)

| PRJNA576496 | ENA

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