Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer
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ABSTRACT:
PROVIDER: PRJNA355634 | ENA |
REPOSITORIES: ENA
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Project description:Therapies that boost the anti-tumor responses of cytotoxic lymphocytes (CTLs) have shown promise in the clinic. However, clinical responses to currently available immunotherapeutic agents vary considerably, for which the molecular basis is unclear. To date, unbiased transcriptomic studies of CTLs in human cancers have been performed in whole tumors or cells obtained from peripheral blood or metastatic sites of heavily pre-treated patients. We performed global transcriptional profiling of CTLs in tumors and adjacent non-tumor tissue from treatment-naïve patients with early stage lung cancer to define the molecular features associated with robustness of anti-tumor immune responses. We observed major differences in the transcriptional program of tumor-infiltrating CTLs that are shared across tumor subtypes. Pathway analysis revealed enrichment of genes in cell cycle, T cell receptor (TCR) activation and co-stimulation pathways, indicating tumor-driven expansion of presumed tumor antigen-specific CTLs. We also observed marked heterogeneity in the expression of molecules associated with TCR activation and immune checkpoints such as 4-1BB, PD1, TIM3, and their expression was positively correlated with the density of tumor-infiltrating CTLs. Interestingly, transcripts linked to tissue-resident memory cells (TRM), such as CD103, were enriched in tumors containing a high density of CTLs, and CTLs from CD103high tumors displayed features of enhanced cytotoxicity, implying better anti-tumor activity. In an independent cohort of 689 lung cancer patients, we confirmed that patients with CD103high (TRM rich) tumors survived significantly longer. In summary, we define the molecular fingerprint of tumor-infiltrating CTLs at the site of primary tumor and identify a number of novel targets that may be important in modulating the magnitude and specificity of anti-tumor immune responses in lung cancer.
2017-06-19 | GSE90729 | GEO
Project description:Therapies that boost the anti-tumor responses of cytotoxic lymphocytes (CTLs) have shown promise in the clinic. However, clinical responses to currently available immunotherapeutic agents vary considerably, for which the molecular basis is unclear. To date, unbiased transcriptomic studies of CTLs in human cancers have been performed in whole tumors or cells obtained from peripheral blood or metastatic sites of heavily pre-treated patients. We performed global transcriptional profiling of CTLs in tumors and adjacent non-tumor tissue from treatment-naïve patients with early stage lung cancer to define the molecular features associated with robustness of anti-tumor immune responses. We observed major differences in the transcriptional program of tumor-infiltrating CTLs that are shared across tumor subtypes. Pathway analysis revealed enrichment of genes in cell cycle, T cell receptor (TCR) activation and co-stimulation pathways, indicating tumor-driven expansion of presumed tumor antigen-specific CTLs. We also observed marked heterogeneity in the expression of molecules associated with TCR activation and immune checkpoints such as 4-1BB, PD1, TIM3, and their expression was positively correlated with the density of tumor-infiltrating CTLs. Interestingly, transcripts linked to tissue-resident memory cells (TRM), such as CD103, were enriched in tumors containing a high density of CTLs, and CTLs from CD103high tumors displayed features of enhanced cytotoxicity, implying better anti-tumor activity. In an independent cohort of 689 lung cancer patients, we confirmed that patients with CD103high (TRM rich) tumors survived significantly longer. In summary, we define the molecular fingerprint of tumor-infiltrating CTLs at the site of primary tumor and identify a number of novel targets that may be important in modulating the magnitude and specificity of anti-tumor immune responses in lung cancer.
2017-06-19 | GSE90728 | GEO
Project description: Not available
| S-EPMC6036910 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-06-19 | GSE90730 | GEO
Project description:Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer [NSCLC]
| PRJNA355638 | ENA
Project description:Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer [HNSCC]
| PRJNA355637 | ENA
Project description:Whereas microglia are recognized as fundamental players in central nervous system (CNS) development and function, much less is known about macrophages of the peripheral nervous system (PNS). Here, by comparing gene expression across neural and conventional tissue-resident macrophages, we identified transcripts that were shared among neural resident macrophages as well as selectively enriched in PNS macrophages. Remarkably, PNS macrophages constitutively expressed genes previously identified to be upregulated by activated microglia during aging, neurodegeneration, or loss of Sall1. Several microglial activation-associated and PNS macrophage-enriched genes were also expressed in spinal cord microglia at steady state. We further show that PNS macrophages rely on IL-34 for maintenance and arise from both embryonic and hematopoietic precursors, while their expression of activation-associated genes did not differ by ontogeny. Collectively, these data uncover shared and unique features between neural resident macrophages and emphasize the role of nerve environment for shaping PNS macrophage identity.
2020-06-01 | GSE146510 | GEO
Project description:Peripheral nerve resident macrophages share tissue-specific programming and features of activated microglia
| PRJNA610789 | ENA
Project description:CD4+ T cells optimize the cytotoxic T cell (CTL) response in magnitude and quality, by unknown molecular mechanisms. We here present the transcriptomic changes, resulting from CD4+ T-cell help during priming, as apparent in effector CTLs. This gene expression signature reveals that CD4+ T-cell help optimizes CTLs in the expression of cytotoxic effector molecules, but also in many other functions that ensure optimal efficacy of CTLs throughout their life cycle.
2017-11-07 | GSE89665 | GEO
Project description:Patients with severe uncontrolled asthma represent a distinct endotype with persistent airway inflammation and remodeling refractory to corticosteroid treatment. CD4+ T cells and their canonical effector molecules, like type 2 cytokines, play a central role in orchestrating asthma pathogenesis, and biologic therapies targeting these cytokine pathways have had promising outcomes. However, not all patients respond well to such treatment, and their effects are not always durable nor reverse airway remodeling. This observation raises the possibility that other CD4+ T cell subsets and their effector molecules may drive airway inflammation and remodeling. To address this issue in a hypothesis-free manner, we performed single-cell transcriptome analysis of >50,000 airway CD4+ T cells isolated from bronchoalveolar lavage (BAL) samples from 30 patients with mild and severe asthma. We observed striking heterogeneity in the nature of CD4+ T cells present in asthmatics' airways with tissue-resident memory (TRM) cells making a dominant contribution. Notably, a subset of CD4+ TRM cells (CD103-expressing) was significantly increased, comprising nearly 65% of all CD4+ T cells in the airways of male patients with severe asthma when compared to mild asthma. This subset was enriched for transcripts linked to T cell receptor (TCR) activation (HLA-DRB1, HLA-DPA1, CD40LG) and cytotoxicity (GZMB, GZMH), and following stimulation expressed high levels of transcripts encoding for pro-inflammatory non-TH2 cytokines (CCL3, CCL4, CCL5, TNF, IL-17A, CSF2, LIGHT) that could fuel persistent airway inflammation and remodeling. Furthermore, we found that CD4+ T cells isolated ex vivo from airways of severe asthmatics displayed signatures linked to corticosteroid resistance (FKBP5, DDIT4), as well as reduced expression of transcripts encoding for molecules that dampen TCR signaling and T cell effector functions (CREM, DUSP1, TNFAIP3). Overall, our single-cell transcriptomic analysis highlights the pathogenic properties and clinical associations of airway CD4+ T cell subsets in severe asthmatics, features that can potentially trigger their unrestrained activation, and that these findings were more pronounced in males. These pathways may therefore be crucial for driving disease severity in adult male severe asthmatics.
2023-10-20 | GSE181709 | GEO