ArticleJournal for immunotherapy of cancer2023
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.
Article in Journal for immunotherapy of cancer, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers, 1 of them a synthesis that pooled it.
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Who cites it
10 citing papers in PubMed, 1 synthesis or guideline pooled it.
- The clinical outcomes of combined stereotactic radiosurgery with PD-1/PD-L1 inhibitors in patients with metastatic brain tumors: a systematic review and meta-analysis on the safety and efficacy.Neurosurgical review · 2025Pooled it
- Anti-PD-1 plus anti-CTLA-4 blockade overcomes immune exclusion in NSCLC brain metastases by enhancing CD8Nature communications · 2026Article
- Adaptive resistance in cancer immunotherapy.Cellular & molecular immunology · 2026Review
- Memory B cell subset shapes antitumor immunity and response to PD-1 blockade in mismatch repair-deficient colorectal cancers.Journal for immunotherapy of cancer · 2026Article
- The toxicity profile and temporal dynamics of dual PD-1/CTLA-4 immune checkpoint blockade: a real-world pharmacovigilance study using the FAERS database.Frontiers in immunology · 2026Article
- Phase IB study of Avelumab and whole brain radiotherapy in patients with leptomeningeal disease from solid tumors: Results and molecular analyses.Neuro-oncology · 2025Article
- Identification of anti-TIM-3 based checkpoint inhibitor combinations with activity in immunotherapy refractory melanoma models.Journal for immunotherapy of cancer · 2025Article
- CTLA-4 and PD-1 combined blockade therapy for malignant melanoma brain metastases: mechanisms, challenges, and prospects.Frontiers in immunology · 2025Review
- Natural killer cells are required for the recruitment of CD8+ T cells and the efficacy of immune checkpoint blockade in melanoma brain metastases.Journal for immunotherapy of cancer · 2024Article
- Systems immunology insights into brain metastasis.Trends in immunology · 2024Review
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9 authors.
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Abstract
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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