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Defining the mechanisms of action to the anti-PD-1+LAG-3 and anti-PD-1+CTLA-4 combinations in melanoma flank models

ABSTRACT: We used single cell (sc) RNA-seq to analyze responding SM1 melanoma flank tumors and SM1 brain metastases to explore the mechanism of action of the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combination.

ORGANISM(S): Mus musculus

PROVIDER: GSE243281 | GEO | 2023/11/10

REPOSITORIES: GEO

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Defining the mechanisms of action to the anti-PD-1+LAG-3 and anti-PD-1+CTLA-4 combinations in melanoma flank models

Project description:Defining the mechanisms of action to the anti-PD-1+LAG-3 and anti-PD-1+CTLA-4 combinations in melanoma flank models

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Differential requirements for CD4+ T cells in the efficacy of the anti-PD-1+LAG-3 and anti-PD-1+CTLA-4 combinations in melanoma flank and brain metastasis models.

Project description:BackgroundAlthough the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combinations are effective in advanced melanoma, it remains unclear whether their mechanisms of action overlap.MethodsWe used single cell (sc) RNA-seq, flow cytometry and IHC analysis of responding SM1, D4M-UV2 and B16 melanoma flank tumors and SM1 brain metastases to explore the mechanism of action of the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combination. CD4+ and CD8+ T cell depletion, tetramer binding assays and ELISPOT assays were used to demonstrate the unique role of CD4+T cell help in the antitumor effects of the anti-PD-1+LAG-3 combination.ResultsThe anti-PD-1+CTLA-4 combination was associated with the infiltration of FOXP3+regulatory CD4+ cells (Tregs), fewer activated CD4+T cells and the accumulation of a subset of IFNγ secreting cytotoxic CD8+T cells, whereas the anti-PD-1+LAG-3 combination led to the accumulation of CD4+T helper cells that expressed CXCR4, TNFSF8, IL21R and a subset of CD8+T cells with reduced expression of cytotoxic markers. T cell depletion studies showed a requirement for CD4+T cells for the anti-PD-1+LAG-3 combination, but not the PD-1-CTLA-4 combination at both flank and brain tumor sites. In anti-PD-1+LAG-3 treated tumors, CD4+T cell depletion was associated with fewer activated (CD69+) CD8+T cells and impaired IFNγ release but, conversely, increased numbers of activated CD8+T cells and IFNγ release in anti-PD-1+CTLA-4 treated tumors.ConclusionsTogether these studies suggest that these two clinically relevant immune checkpoint inhibitor (ICI) combinations have differential effects on CD4+T cell polarization, which in turn, impacted cytotoxic CD8+T cell function. Further insights into the mechanisms of action/resistance of these clinically-relevant ICI combinations will allow therapy to be further personalized.

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Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade [WES]

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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Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade [RNA-seq]

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Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade

Project description:Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade

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Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking

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Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8 T cells [dataset 4]

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Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8 T cells [dataset 3]

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