FCRL4 and exhausted B cell signature in tumor infiltrating B cells from lung cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1213104 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32053000_1.fastq.gz | Fastqsanger.gz | |||
| SRR32053000_2.fastq.gz | Fastqsanger.gz | |||
| SRR32053001_1.fastq.gz | Fastqsanger.gz | |||
| SRR32053001_2.fastq.gz | Fastqsanger.gz | |||
| SRR32053002_1.fastq.gz | Fastqsanger.gz |
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Project description:Our understanding of the heterogeneity of tumor-infiltrating B cells (TIBs) evolves in parallel with the advances in high-dimensional flow cytometry and single-cell RNA sequencing (scRNA-seq). Subpopulations of TIBs have been described with diverse and even opposite roles in tumor control, based on surface molecule, cytokine and transcriptional factor expression. Furthermore, recently the predictive role of IgA and IgG expression in tumors was shown for melanoma and KRAS-mutated, but not KRAS wild type, lung adenocarcinoma. This may imply that B cells producing different immunoglobulin isotypes also acquire different functional characteristics that have unequal effects on tumor microenvironment (TME) and differentially affect tumor progression. To address this question, we performed comparative bulk transcriptome analysis of tumor-infiltrating surface-IgA+ (sIgA+) and sIgG+ memory B cells from lung adenocarcinoma (LUAD) tumors. We identified FCRL4, PDCD1 and RUNX2 among genes overexpressed in IgA+ B cells, which suggests exhausted, chronically antigen-stimulated phenotype. Using public scRNA-seq data, we showed that FCRL4-expressing memory TIBs form a distinct cluster of cells with transcriptomic profile characterized by upregulation of genes involved in IFNγ and IFNα responses. sIgG+ B cells, on the other hand, overexpress IL5RA, consistent with the role of IL-5 in class-switch recombination to IgG isotype. Moreover, based on the analysis of the TCGA LUAD cohort, we found that FCRL4 to CD20 expression ratio correlates with lower overall survival, further strengthening the view on FCRL4 as a marker of exhausted dysfunctional TIBs. Our findings support the initial hypothesis that IgA/IgG ratio in tumors is not merely an indication of cytokine environment in the TME, but also reflects the difference in the functional characteristics of the respective B cell populations.
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Project description:Fresh human breast tumor tissue was dissociated into single cells and viably frozen. Patient samples were annotated as having an ""exhausted"" or ""non-exhausted"" immune environment based on CyTOF characterization of T cell phenotypes (Wagner et al, Cell 2019). 14 samples (7 exhausted, 7 non-exhausted) were selected for scRNA-seq (without prior cell type enrichment) with the goal to compare the two immune environment types and to comprehensively characterize exhaustion-associated features of the tumor microenvironment.
2023-08-25 | E-MTAB-10607 | biostudies-arrayexpress
Project description:RELB Reprograms Exhausted Tumor-Infiltrating Lymphocytes for Improved Adoptive Cell Therapy [proliferation]
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Project description:CD8+ tumor infiltrating lymphocytes (TILs) are associated with improved survival in triple negative breast cancer (TNBC), yet have no association with survival in estrogen receptor-positive (ER+) BC. The basis for these contrasting findings remains elusive. We identify subsets of BC tumors infiltrated by CD8+ T cells with characteristic features of exhausted T cells (TEX). Tumors with abundant CD8+ TEX exhibit a distinct tumor microenvironment marked by amplified interferon-γ signaling related pathways and higher PD-L1 expression. Paradoxically, high levels of CD8+ TEX TILs associate with decreased overall survival ER+ BC patients, but not TNBC patients. Moreover, high tumor expression of a CD8+ TEX signature identifies dramatically reduced survival in pre-menopausal, but not post-menopausal, ER+ BC patients. Finally, we demonstrate the value of a tumor TEX signature score in identifying high-risk pre-menopausal ER+ BC patients amongst those with intermediate Oncotype Dx breast recurrence scores. Our data highlight the complex relationship between CD8+ TILs, interferon-γ signaling, and estrogen receptor status in BC patient survival. This work identifies pre-menopausal ER+ BC patients with high levels of tumor infiltrating CD8+ TEX as a high-risk subset that may benefit from immunotherapy strategies.
2022-02-23 | GSE190202 | GEO
Project description:Tumor-infiltrating lymphocytes (TILs) are a promising autologous cell therapy to treat solid tumors. TILs are manufactured by expanding and reinfusing tumor-reactive T cells from tumor biopsies. Efficacy of TIL therapies has been limited by the heterogeneity of expanded TIL products and the high prevalence of dysfunctional exhausted CD8+ T cells (TEX). A subset of CD8+ TILs that are double-positive (DP) for CD103 and CD39 is enriched for tumor-reactive TILs across multiple cancer types, but also is susceptible to the TEX state. We screened overexpression of all human transcription factors (TFs) to discover master regulators of expansion in DP TILs from non-small cell lung cancer patients. RELB emerged as the dominant hit driving proliferation of DP TILs despite exhaustion induced by repeat stimulation, with a skew towards CD8+ cells. TCR-seq showed maintenance of TCR diversity from the initial TCR repertoire after multiple days of in vitro expansion driven by RELB. Transcriptome profiling of multiple RELB-expressing TIL subtypes revealed a shift towards a memory/costimulatory-like phenotype. Using a HER2-targeting CAR and tumor co-culture model, RELB conferred improved persistence after multiple tumor challenges in vitro and improved solid tumor control in mouse xenografts in vivo. Finally, co-culture of RELB-overexpressing TILs with patient-matched tumor organoids showed an increase in TIL product polyfunctionality, tumor reactivity, and tumor killing.
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Project description:Background: Although tumor-infiltrating T cells represent a favorable prognostic marker for cancer patients, the majority of these cells are rendered with an exhausted phenotype. Hence, there is an unmet need to identify factors which can reverse this dysfunctional profile and restore their anti-tumorigenic potential. Activin-A is a pleiotropic cytokine, exerting a broad range of pro- or anti-inflammatory functions in different disease contexts, including allergic and autoimmune disorders and cancer. Given that activin-A exhibits a profound effect on CD4+ T cells in the airways and is elevated in lung cancer patients, we hypothesized that activin-A can effectively regulate anti-tumor immunity in lung cancer. Methods: To evaluate the effects of activin-A in the context of lung cancer, we utilized the OVA-expressing Lewis Lung Carcinoma mouse model as well as the B16F10 melanoma model of pulmonary metastases. The therapeutic potential of activin-A-treated lung tumor-infiltrating CD4+ T cells was evaluated in adoptive transfer experiments, using CD4-/--tumor bearing mice as recipients. In a reverse approach, we disrupted activin-A signaling on CD4+ T cells using an inducible model of CD4+ T cell-specific knockout of activin-A type I receptor. RNA-Sequencing analysis was performed to assess the transcriptional signature of these cells and the molecular mechanisms which mediate activin-A’s function. In a translational approach, we validated activin-A’s anti-tumorigenic properties using primary human tumor-infiltrating CD4+ T cells from lung cancer patients. Results: Administration of activin-A in lung tumor-bearing mice attenuated disease progression, an effect associated with heightened ratio of infiltrating effector to regulatory CD4+ T cells. Therapeutic transfer of lung tumor-infiltrating activin-A-treated CD4+ T cells, delayed tumor progression in CD4-/- recipients and enhanced T cell-mediated immunity. CD4+ T cells genetically unresponsive to activin-A, failed to elicit effective anti-tumor properties and displayed an exhausted molecular signature governed by the transcription factors Tox and Tox2. Of translational importance, treatment of activin-A on tumor-infiltrating CD4+ T cells from lung cancer patients augmented their immunostimulatory capacity towards autologous CD4+ and CD8+ T cells. Conclusions: In this study, we introduce activin-A as a novel immunomodulatory factor in the lung tumor microenvironment, which bestows exhausted CD4+ T cells with effector properties.
2021-09-10 | GSE183544 | GEO
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2025-12-02 | GSE303438 | GEO
Project description:Tumor-infiltrating lymphocytes (TILs) are a promising autologous cell therapy to treat solid tumors. TILs are manufactured by expanding and reinfusing tumor-reactive T cells from tumor biopsies. Efficacy of TIL therapies has been limited by the heterogeneity of expanded TIL products and the high prevalence of dysfunctional exhausted CD8+ T cells (TEX). A subset of CD8+ TILs that are double-positive (DP) for CD103 and CD39 is enriched for tumor-reactive TILs across multiple cancer types, but also is susceptible to the TEX state. We screened overexpression of all human transcription factors (TFs) to discover master regulators of expansion in DP TILs from non-small cell lung cancer patients. RELB emerged as the dominant hit driving proliferation of DP TILs despite exhaustion induced by repeat stimulation, with a skew towards CD8+ cells. TCR-seq showed maintenance of TCR diversity from the initial TCR repertoire after multiple days of in vitro expansion driven by RELB. Transcriptome profiling of multiple RELB-expressing TIL subtypes revealed a shift towards a memory/costimulatory-like phenotype. Using a HER2-targeting CAR and tumor co-culture model, RELB conferred improved persistence after multiple tumor challenges in vitro and improved solid tumor control in mouse xenografts in vivo. Finally, co-culture of RELB-overexpressing TILs with patient-matched tumor organoids showed an increase in TIL product polyfunctionality, tumor reactivity, and tumor killing.
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