CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumors.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA693857 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13500400_1.fastq.gz | Fastqsanger.gz | |||
| SRR13500400_2.fastq.gz | Fastqsanger.gz | |||
| SRR13500500_1.fastq.gz | Fastqsanger.gz | |||
| SRR13500500_2.fastq.gz | Fastqsanger.gz | |||
| SRR13500401_1.fastq.gz | Fastqsanger.gz |
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Project description:CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumors
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Project description:Immune checkpoint blockade is able to achieve durable responses in a subset of patients, however we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. To address these issues we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint blockade induced immune responses are driven by distinct cellular mechanisms.
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Project description:Immune checkpoint blockade (ICB) therapy has demonstrated promising clinical results in oncology and is currently one of the most sought-after immunotherapies for tumors. However, there are a number of issues with ICB therapy, including low response rates and a lack of effective efficacy predictors. Gasdermin-mediated pyroptosis is a typical form of inflammatory death mode, but it is unclear whether ICB treatment can trigger its occurrence or whether gasdermin expression has any effect on the response rate to ICB treatment. Herein, we discovered that high expression of gasdermin protein was associated with a favorable tumor immune microenvironment and a favorable prognosis in head and neck squamous cell carcinoma (HNSCC), and taking advantage of the mouse HNSCC cell line 4MOSC1 (responsive to CTLA-4 blockade) and 4MOSC2 (resistant to CTLA-4 blockade) orthotopic models, we also demonstrated that CTLA-4 blockade treatment induced gasdermin-mediated pyroptosis of tumor cells and that the expression of gasdermin was positively associated with the effectiveness of CTLA-4 blocking treatment. Mechanistically, through RNA sequencing, flow cytometry, ELISA, Western blotting and RT-PCR, we discovered that CTLA-4 blockade activated CD8+ T cells in the tumor and increased the levels of the cytokines TNF-α and IFN-γ in the tumor microenvironment, and that TNF-α and IFN-γ synergistically activated the STAT1/IRF1 axis, inducing tumor cell pyroptosis and the release of large amounts of inflammatory substances and chemokines such as CXCL10.
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Project description:T cells receive numerous positive and negative signals during primary antigen encounter that control their proliferation and function, but how these signals are integrated to modulate T cell memory has not been fully characterized. In these studies, we demonstrate that combining seemingly opposite signals, CTLA-4 blockade and rapamycin-mediated mTOR inhibition, during in vivo T cell priming leads to both an increase in the frequency of memory CD8+ T cells and improved memory responses to tumors and bacterial challenges. This enhanced efficacy corresponds to increased early expansion and memory precursor differentiation of CD8+ T cells and increased mitochondrial biogenesis and spare respiratory capacity in memory CD8+ T cells in mice treated with anti-CTLA-4 and rapamycin during immunization. Collectively, these results reveal that mTOR inhibition cooperates with rather than antagonizes blockade of CTLA-4, promoting unrestrained effector function and proliferation and an optimal metabolic program for CD8+ T cell memory.
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