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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]

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: GSE218004 | 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 [ChIP-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 | GSE218005 | GEO

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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

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2024-12-02 | GSE263351 | GEO

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