CD8+ T cells regulate tumor ferroptosis during cancer immunotherapy
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ABSTRACT:
PROVIDER: PRJNA527311 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR8734984_1.fastq.gz | Fastqsanger.gz | |||
| SRR8734984_2.fastq.gz | Fastqsanger.gz | |||
| SRR8734985_1.fastq.gz | Fastqsanger.gz | |||
| SRR8734985_2.fastq.gz | Fastqsanger.gz | |||
| SRR8734986_1.fastq.gz | Fastqsanger.gz |
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Project description:CD8+ T cells activated by cancer immunotherapy execute tumor clearance mainly by inducing cell death through perforin-granzyme- and Fas/Fas ligand-pathways. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent lipid peroxide accumulation. Although it was mechanistically illuminated in vitro, emerging evidence has shown that ferroptosis may be implicated in a variety of pathological scenarios. However, the involvement of ferroptosis in T cell immunity and cancer immunotherapy is unknown. Here, we find that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumor cells, and in turn, increased ferroptosis contributes to the anti-tumor efficacy of immunotherapy. Mechanistically, IFNg released from CD8+ T cells downregulates expression of SLC3A2 and SLC7A11, two subunits of glutamate-cystine antiporter system xc-, restrains tumor cell cystine uptake, and as a consequence, promotes tumor cell lipid peroxidation and ferroptosis. In preclinical models, depletion of cyst(e)ine by cyst(e)inase in combination with checkpoint blockade synergistically enhances T cell-mediated anti-tumor immunity and induces tumor cell ferroptosis. Thus, T cell-promoted tumor ferroptosis is a novel anti-tumor mechanism. Targeting tumor ferroptosis pathway constitutes a therapeutic approach in combination with checkpoint blockade.
2019-03-16 | GSE128392 | GEO
Project description:Despite the successful application of immunotherapy, both innate and acquired resistance are typical in melanoma. Ferroptosis induction appears to be a potential strategy to enhance the effectiveness of immunotherapy. However, the relationship between the status of ferroptosis and the effectiveness of immunotherapy, as well as viable strategies to augment ferroptosis, remain unclear. In this study, through large-scale drug screening of cardiovascular drugs, we identified propafenone, an anti-arrhythmia medication, as capable of synergizing with ferroptosis inducers in melanoma. Furthermore, we observed that propafenone, in combination with RSL3, collaboratively induces mitochondrial-associated ferroptosis. Mechanistically, propafenone transcriptionally upregulates mitochondrial HMOX1 via activation of the JNK/JUN signaling pathway under RSL3 treatment, leading to overloaded ferrous iron and ROS within the mitochondria. In xenograft models, the combination of propafenone with ferroptosis induction led to nearly complete tumor regression. Consistently, propafenone enhances immunotherapy-induced antitumor immunity and tumoral ferroptosis in tumor-bearing mice. Significantly, patients exhibiting high levels of ferroptosis/JUN/HMOX1 exhibited improved efficacy of immunotherapy and prolonged progression-free survival. These findings suggest that propafenone holds promise as a candidate drug for enhancing the efficacy of immunotherapy and other ferroptosis-targeted therapies in the treatment of melanoma.
2024-10-26 | GSE279924 | GEO
Project description:Cancer immunotherapy restores or enhances the effector function of CD8+ T cells in the tumour microenvironment1,2. CD8+ T cells activated by cancer immunotherapy clear tumours mainly by inducing cell death through perforin-granzyme and Fas-Fas ligand pathways3,4. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide5,6. Although it has been investigated in vitro7,8, there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios9,10. It is unclear whether, and how, ferroptosis is involved in T cell immunity and cancer immunotherapy. Here we show that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFNγ) released from CD8+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system xc-, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system xc- was negatively associated, in cancer patients, with CD8+ T cell signature, IFNγ expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.
| S-EPMC6533917 | biostudies-literature
Project description:CD8 T cells isolated from blood of mice treated with radiation therapy and immunotherapy
2024-06-20 | PXD043110 | JPOST Repository
Project description:Radiotherapy (RT) destroys tumor cells, which may lead to release of antigens and immune-activating signals. In this way, RT may act as an in situ vaccine and kick-start a T-cell response against the tumor. Immunotherapy enhances tumor-specific T-cell responses. Combination of radiotherapy and immunotherapy (radio-immunotherapy (RIT)) can therefore be expected to synergize in inducing and sustaining systemic anti-tumor T-cell responses. However, in the clinic, systemic combined responses between radiotherapy and immunotherapy are rarely observed, as the effect of RIT combinations on ‘abscopal’ tumors outside the radiotherapy field are not (yet) greater than the effect of immunotherapy alone. In order to define potential bottlenecks in the tumor micro-environment that impede CD8 T cell activity, we harvested irradiated and non-irradiated tumors from the same mice that were treated with RIT (10 Gy RT, anti-CD137 and anti-PD1). From these tumors, effector (CD43+) CD8 T cells, ‘other’ hematopoietic (CD45+) cells and tumor/stromal (CD45-) were sorted and RNA sequencing was performed to identify differences between these cell populations in the irradiated and non-irradiated tumors that could explain the lack of T cell activity in the non-irradiated tumor.
2019-02-12 | E-MTAB-6914 | biostudies-arrayexpress
Project description:Anti-PD-1 immunotherapy has been established to be greatly effective in melanoma treatment, but the low response rate and occurrence of treatment resistance significantly hinder its efficacy. Recent studies have demonstrated that IFN-γ secreted by tumor-infiltrating CD8+T cells suppresses the expression of Xc- system to induce ferroptosis of tumor cells. However, whether the escape of tumor cells from ferroptosis facilitates the resistance to immunotherapy and the upstream regulatory mechanism remain elusive. MiRNAs participate in ferroptosis execution and can be delivered systemically by nanoparticle or alternative carriers, through which obvious therapeutic effect on cancer has been obtained. Herein, through RNA sequencing, we first obtained miRNAs expression profile of melanoma cells in IFN-γ-potentiated ferroptosis.
2022-06-29 | GSE186497 | GEO
Project description:Immunotherapy has opened hitherto unknown possibilities to treat cancer. Whereas some cancer types (e.g. melanoma) can be efficiently treated, others lack measurable positive effects (e.g. PDAC). Moreover, stratification of responders/non-responders is only possible in some cancer types (e.g. melanoma). Hepatocellular carcinoma (HCC) has a dismal prognosis, limited treatment options and survival benefit, and represents a potential cancer entity for successful immunotherapy. Here, we investigated NASH-triggered HCC in the context PD-1-targeted immunotherapy. Using flow cytometry, single cell RNA sequencing, immunohistochemistry and mass spectrometric analyses, we found a progressive increase of CD8+PD-1+ effector T-cells with a unique profile of exhaustion and activation markers rising with murine and human NASH severity. Notably, late-stage HCC treatment with PD-1-targeted immunotherapy enhanced hepatic carcinogenesis in mice. Dissecting potential mechanisms of action during tumor-initiation and -progression we analyzed the effects of PD-1-targeted immunotherapy at HCC initiation. PD-1-targeted immunotherapy induced a pro-tumorigenic environment, enhanced necro-inflammation and increased NAFLD-activation score (NAS), leading to increased liver cancer incidence, tumor number and nodule size. In contrast, anti-CD8 or anti-CD8/anti-NK1.1 treatment reduced NAS and abrogated the development of liver cancer, thus identifying CD8+PD-1+ T-cells as drivers of liver cancer in NASH-triggered HCC. Increased apoptotic signaling, STAT3 phosphorylation and hepatic proliferation were detected in intra-tumoral liver tissue upon PD-1-targeted immunotherapy. In line, PD-1-/- mice challenged with a NASH diet displayed early onset of hepatocarcinogenesis, corroborating the pro-tumorigenic role of absent or reduced PD-1. Mechanistically PD-1-targeted immunotherapy mainly affected hepatic abundance of CD8+PD-1+ T-cells, instead of altering the quality of Tox+CXCR6+ expressing CD8+PD-1+TNF+CD39+Gzmb+ T-cells found in NASH livers, leading to an aggressive, pro-tumorigenic liver environment. Single-cell mapping of human NASH-, borderline NASH- or unaffected livers corroborated our preclinical NASH results. Moreover, in human NASH livers a correlation of hepatic CD8+, PD-1+, TNF+ T-cells with fibrosis and NASH severity was observed. Accordingly, HCC patients with NASH etiology display a sharp increase in intra- and peri-tumoral CD8+ PD-1+ T-cells. In a cohort of 65 patients recruited across 6 centers in Germany and Austria, patients with NAFLD/NASH-driven HCC responded worse to PD-1-targeted immunotherapy by Nivolumab or Pembrolizumab compared to non-NAFLD patients. This resulted in significant reduced overall survival, in trends of faster disease progression and reduced progression free survival. Histological analysis of livers derived from HCC patients treated with PD-1-targeted immunotherapy displayed high levels of intra and peri-tumoral CD8+ PD-1+ T-cells and Ki67+ hepatocytes. Taken together, these data indicate that PD-1-targeted immunotherapy induces immune-related adverse effects in NAFLD/NASH-driven HCC through CD8+PD-1+ T-cells. Our data call for stratification of HCC patients subjected to PD-1-targeted immunotherapy, with NAFLD being a negative predictor.
2021-03-03 | PXD017236 | Pride
Project description:Gastric adenocarcinoma (GAC) remains a significant cause of cancer-related deaths worldwide, with the majority of mortality resulting from metastatic spread. To elucidate the evolution of cancer cells and their interactions with the tumour microenvironment (TME), we conducted a comprehensive single-cell transcriptome and immune repertoire profiling of primary tumours (PRIs), matched liver metastases (LMs) or peritoneal carcinomatosis (PC), adjacent normal tissues, and blood samples from 20 treatment-naïve patients. We found that the TME within metastases varied substantially from PRIs and differed between LMs and PC samples. Indicative of immune evasion, we observed diminished T cell clonal expansion, a marked reduction in the fraction of tumour-reactive CD8 T cells, and an enrichment of naïve T cells, M2-like, and proliferative macrophages in PC samples compared to PRIs. LMs displayed significantly reduced B cells, with increased fractions of exhausted CD8 T cells and NK/NKT cells. Both LMs and PC showed nearly depleted plasma cells. Malignant cells largely exhibited diminished gastric lineage identity, predominantly adopting intestinal-like and mixed cell states, with the acquired expression of gastrointestinal stem-cell markers. LM cancer cells showed increased epithelial-to-mesenchymal signalling, while PC cancer cells had increased levels of aneuploidy. We observed differentially expressed cancer meta-programs and gene modules (GMs) between LMs and PC, with high GM2 expression in the PRI predicting an increased risk of distant metastases. Further analysis of GM signature genes revealed ferroptosis evasion through GPX4 upregulation during malignant progression. Functional validation via patient-derived xenografts and a novel autochthonous mouse model of GAC confirmed that genetic or pharmacological inhibition of ferroptosis resistance attenuates tumor growth and metastatic progression. Together, our mapping of malignant progression provides a rationale for targeting ferroptosis defense in combination with next-generation CAR T-cell immunotherapy as a potential avenue to overcome T cell dysfunction in advanced metastatic GAC therapy.
2024-05-23 | GSE239676 | GEO
Project description:Tumor-specific CD8+ T cells are heterogeneous; Tcf1+ stem-like CD8+ T cells give rise to cytotoxic Tim-3+ terminally differentiated CD8+ T cells. The goal of this study is to determine the capacity of CD69 to regulate differentiation of tumor-specific CD8+ T cells in the tumor microenvironment and tumor-draining lymph nodes. Our single-cell RNA-seq and RNA-seq analyses of tumor-specific CD8+ T cells reveal the important function of CD69 in anti-tumor CD8+ T cell immunity. Thus, CD69 is an attractive target for cancer immunotherapy.
2023-03-29 | GSE228387 | GEO
Project description:Tumor-specific CD8+ T cells are heterogeneous; Tcf1+ stem-like CD8+ T cells give rise to cytotoxic Tim-3+ terminally differentiated CD8+ T cells. The goal of this study is to determine the capacity of CD69 to regulate differentiation of tumor-specific CD8+ T cells in the tumor microenvironment and tumor-draining lymph nodes. Our single-cell RNA-seq and RNA-seq analyses of tumor-specific CD8+ T cells reveal the important function of CD69 in anti-tumor CD8+ T cell immunity. Thus, CD69 is an attractive target for cancer immunotherapy.
2023-03-29 | GSE228386 | GEO