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CD4 Polarized T cells Reduce the Expansion of Tumor Infiltrating Lymphocytes in Melanoma Patients Treated with Adoptive Cell Therapy [ChIP-seq]

ABSTRACT: Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) is effective in treating PD-1 refractory melanoma, but requires adequate ex vivo expansion of TIL. Methods: CD4+ and CD8+ TIL from metastatic melanoma patients treated with TIL ACT were analyzed by RNA-seq (n=12) and ChIP-seq of acetylated histone 3 (n=19). Patients were grouped into “TIL high” and “TIL low” based on division at the median number of TIL infused. The number of TIL infused and CD4+ TIL frequency were correlated with overall survival (OS). Results: The number of TIL infused correlated with longer OS (R2=0.57, p=0.00076), and the percent of CD4+ infused was negatively correlated with the total number of TIL infused (R2=0.64, p=0.00047). RNA-seq analysis of CD4+ TIL showed increases in Th2/Th17/Treg transcripts and pathways in the TIL low group. ChIP-seq analysis of CD8+ TIL showed decreased acetylation in the TIL low group in genes upregulated during CD8+ activation. Conclusion: The numbers of TIL infused were associated with increased overall survival, while RNA-seq suggested that polarized CD4+ cells in the transferred TIL were associated with decreased overall expansion. These data suggest that improper CD4+ TIL polarization may reduce expansion and treatment efficacy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218005 | GEO | 2023/07/17

REPOSITORIES: GEO

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CD4 Polarized T cells Reduce the Expansion of Tumor Infiltrating Lymphocytes in Melanoma Patients Treated with Adoptive Cell Therapy [RNA-seq]

Project description:Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) is effective in treating PD-1 refractory melanoma, but requires adequate ex vivo expansion of TIL. Methods: CD4+ and CD8+ TIL from metastatic melanoma patients treated with TIL ACT were analyzed by RNA-seq (n=12) and ChIP-seq of acetylated histone 3 (n=19). Patients were grouped into “TIL high” and “TIL low” based on division at the median number of TIL infused. The number of TIL infused and CD4+ TIL frequency were correlated with overall survival (OS). Results: The number of TIL infused correlated with longer OS (R2=0.57, p=0.00076), and the percent of CD4+ infused was negatively correlated with the total number of TIL infused (R2=0.64, p=0.00047). RNA-seq analysis of CD4+ TIL showed increases in Th2/Th17/Treg transcripts and pathways in the TIL low group. ChIP-seq analysis of CD8+ TIL showed decreased acetylation in the TIL low group in genes upregulated during CD8+ activation. Conclusion: The numbers of TIL infused were associated with increased overall survival, while RNA-seq suggested that polarized CD4+ cells in the transferred TIL were associated with decreased overall expansion. These data suggest that improper CD4+ TIL polarization may reduce expansion and treatment efficacy.

2023-07-17 | GSE218004 | GEO

Impact of CD4+ T cell help on CD8+ CAR T cell gene expression during ex-vivo manufacturing

Project description:Cell culture conditions impact the clinical efficacy of chimeric antigen receptor (CAR) T cell products, but the optimal approach remains unknown. Separate CD4+ and CD8+ cultures offer a potential advantage but complicate manufacturing and may affect cell expansion and function. We evaluated the co-culture of CD4+ and CD8+ cells at a defined ratio at culture initiation. We observed that the presence of CD4+ cells markedly improves expansion of CD8+ CAR T cells, and CD8+ cells cultured in isolation exhibit a hypofunctional phenotype and transcriptional signature compared with those co-cultured with CD4+ cells. Mixed-culture CAR T cells also confer superior anti-tumor activity in vivo compared with separately expanded, co-infused cells. CD4+ cell effects on CD8+ cells are mediated through both cytokines and direct cell contact, including CD40L-CD40 and CD70-CD27 interactions.

2023-11-30 | GSE245427 | GEO

RNA Profiling in Patients' tumor infiltrating lymphocytes

Project description:Identifying tumor antigen-specific T cells from cancer patients has been a goal of tumor immunologists for several decades. Co-expression of CD103 and CD39 on CD8 TIL highly enriches for tumor-reactive T cells. CD39+CD103+ CD8 TIL have a distinct TCR repertoire compared to other CD8 TIL subsets and are clonally expanded within the tumor. They are highly enriched for tumor antigen recognition and efficiently killed autologous tumor cells. Patients with head and neck cancer whose CD8 TIL contained a higher frequency of CD39+CD103+ cells experienced a greater overall survival. This work describes a simple and effective method for detecting tumor-reactive CD8 TIL.

2018-05-26 | GSE114944 | GEO

Adoptive Cell Therapy Using Cancer Specific CD8+ Tumor Infiltrating Lymphocytes in Adult Patients With Solid Tumors

Project description:The subject of this study is the adoptive transfer of selected autologous tumor infiltrating lymphocytes (TIL) after in vitro expansion for the treatment of solid tumor malignancies. The TIL selection process is based on evidence showing that CD8+ TIL which co-express both CD39 and CD103 harbor the bulk of tumor-reactivity and that the remaining CD8 TIL is mainly composed of non-tumor reactive bystander cells. All of the expanded TIL that are produced (1-40 billion are expected) will be delivered in the form of a cell suspension to the participants by intravenous infusion. It is proposed that these selected TIL will produce a more potent and efficacious treatment of late-stage cancer.

| 63320 | ecrin-mdr-crc

Immune Signatures and Tumor Biomarkers from Whole Transcriptome Sequencing Predict Outcome in Recurrent Resectable Stage III and IV Melanoma when Evaluated Following Treatment with Hu14.18-IL2

Project description:We analyzed whole transcriptome sequencing in tumors from 23 patients with stage III or IV melanoma from a pilot trial of the anti-GD2 immunocytokine, hu14.18-IL2, in melanoma patients at high risk for recurrence to identify predictive immune and/or tumor biomarkers. Patients with advanced resectable melanoma were randomized to receive the first of 3 monthly-courses of hu14.18-IL2 immunotherapy either before (Group A) or after (Group B) complete surgical resection of all known disease. Tumors were evaluated by histology, immunohistochemistry and whole transcriptome sequencing. We report here that tumor infiltrating lymphocyte (TIL) levels directly correlate with relapse-free-survival (RFS) and overall-survival (OS). Resected tumors from Group A, but not Group B, patients demonstrated a direct correlation between TIL levels and survival. TIL levels directly correlated with a previously Estimated RNAseq-determined Immune Signature (EIS). This EIS correlated with RFS and OS, particularly in Group A tumors. Group A tumors demonstrated decreased cell cycling RNA gene transcripts, but increased RNA gene transcripts associated with repair and growth. Additionally, we found several direct correlations of immune signatures and immune related RNA transcripts as well as many inverse correlations of tumor growth-associated transcripts with RFS and OS, particularly in Group A tumors. Most of these correlations were not seen in Group B tumors. We interpret these data to signify that both immunologic and tumoral cell processes, as measured by RNAseq analyses, are associated with long term survival after hu14.18-IL2 therapy and could potentially be prognosticated using neoadjuvant treatment resection specimens obtained after initiating immunotherapy.

2020-07-01 | GSE133713 | GEO

CD4+CD+8 double positive T-cell mRNA expression profiles from patients with granulomatotis with polyangiitis (GPA) compared to healthy controls

Project description:Expansion of circulating CD4+CD8+ double positive (DP) T-cells in a disease context is poorly understood. The study aims to identify mechanisms which may drive expansion of CD4+CD8+ double positive t-cells in GPA. PBMCs from 3 GPA patients and 3 healthy controls were used to generate mRNA profiles from CCD4+CD8+ double positive T-cells in a disease context

2014-10-03 | E-GEOD-56481 | biostudies-arrayexpress

Molecular profile of tumor-specific CD8+ T cell hypofunction in cancer

Project description:Comparison of genome-wide mRNA expresson between tumor-infiltrating CD8+ T cells from the tumor (hypofunctional T cells) and periphery (functional T cells) Mechanisms of self-tolerance often result in CD8+ tumor-infiltrating lymphocytes (TIL) with a hypofunctional phenotype incapable of tumor clearance. Using a solid tumor model in mice, we found that CD8+ T cells became tolerized in less than 24 hours in an established tumor environment. To define the collective impact of pathways suppressing TIL function, we compared genome-wide mRNA expression of tumor-specific CD8+ T cells from the tumor and periphery. Notably, gene expression induced during TIL hypofunction more closely resembled self-tolerance than viral-exhaustion. Differential gene expression was refined to identify a core set of genes that defined hypofunctional TIL; these data comprise the first âmolecular profileâ of tumor-specific TIL that are naturally responding and represent a polyclonal repertoire. The molecular profile of TIL was further dissected to determine the extent of overlap and distinction between pathways that collectively restrict T cell functions. As suggested by the molecular profile of TIL, protein expression of inhibitory receptor LAG-3 was differentially regulated throughout prolonged late-G1/early-S phase of the cell cycle. Our data may accelerate efficient identification of combination therapies to boost anti-tumor function of TIL specifically against tumor cells. 4 samples, 3 biological replicates per group.

2016-04-03 | E-GEOD-79858 | biostudies-arrayexpress

Effect of Perioperative Immune Status and Long-term Prognosis of Thymosin Alpha-1 for Injection(Zadaxin) in Treatment of Patients with Colorectal Cancer: A Prospective, Randomized Controlled Trial

Project description:Interventions: Test group:Thymosin Alpha-1 subcutaneous injection;Control group:without Thymosin alpha-1 Primary outcome(s): CD4 / CD8 ratio;CRP;PLR;NLR;1-year DFS;3-year DFS;2-year OS Study Design: Parallel

| 36170 | ecrin-mdr-crc

Immediate dysfunction of vaccine-elicited CD8+ T cells primed in the absence of CD4+ T cells

Project description:CD4+ T cell help is critical for optimal CD8+ T cell expansion after priming in many experimental systems. However, a role for CD4+ T cells in regulating the initial steps of CD8+ T cell effector differentiation is not well established. Here we demonstrate that absence of CD4+ T cells at the time of replication-incompetent adenovirus vector immunization of C57BL/6 mice led to immediate CD8+ T cell dysfunction characteristic of exhaustion at the first detectable timepoints as well as impaired expansion of antigen-specific CD8+ T cells. The absence of CD4+ T cell help resulted in antigen-specific CD8+ T cells that had reduced ex vivo cytotoxicity and decreased capacity to produce IFN-Î³ and TNF-Î±. CD8+ T cells primed in the absence of CD4+ T cells expressed elevated levels of the inhibitory receptors PD-1, LAG-3, and Tim-3, and these cells exhibited transcriptomic exhaustion profiles by gene set enrichment analysis. This dysfunctional state was imprinted within 3 days of immunization and could not be reversed by provision of CD4+ T cell help after priming. Partial rescue of unhelped CD8+ T cell expansion and effector differentiation could be achieved by PD-1 pathway blockade or recombinant IL-2 administration. This study identifies a novel, previously undescribed role of CD4+ T cells to prevent immediate dysfunction and features of exhaustion in CD8+ T cells following antigen priming. Splenic AL11-specific CD8 T cells from mice immunized with Ad5HVR48(1-7)-SIV Gag and treated with anti-CD4 antibody or not were purified by FACS on day 14 post-immunization

2016-07-01 | E-GEOD-73001 | biostudies-arrayexpress

CD28 Co-stimulation Drives Tumor-Infiltrating T Cell Glycolysis to Promote Inflammation

Project description:Metabolic reprogramming dictates the fate and function of stimulated T cells, yet these pathways can be suppressed in T cells subjected to unique microenvironments, such as in a tumor. We previously showed that glycolytic and mitochondrial adaptations directly contribute to reduced effector functions of Renal Cell Carcinoma (RCC) CD8 tumor infiltrating lymphocytes (TIL). Here we define the role of these metabolic pathways in the activation and effector functions of RCC CD8 TIL. CD28 co-stimulation plays a key role to augment T cell activation and metabolism and is antagonized by inhibitory and checkpoint immunotherapy receptors CTLA4 and PD-1. While RCC CD8 TIL activated poorly when stimulated through the T cell receptor alone, addition of CD28 co-stimulation greatly enhanced activation, function, and proliferation. CD28 co-stimulation reprogrammed RCC CD8 TIL metabolism with increased glycolysis and mitochondrial oxidative metabolism, in part through upregulation of GLUT3. Mitochondria also became more fused, with higher membrane potential and overall mass. These phenotypes were dependent on glucose metabolism, as the glycolytic inhibitor 2-deoxyglucose both prevented changes to mitochondria and suppressed RCC CD8 TIL activation and function. These data show that CD28 co-stimulation can restore RCC CD8 TIL metabolism and function through rescue of T cell glycolysis that supports mitochondrial mass and activity.

2020-08-10 | GSE151669 | GEO

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