ArticleNeoplasia (New York, N.Y.)2019
Dual CTLA-4 and PD-L1 Blockade Inhibits Tumor Growth and Liver Metastasis in a Highly Aggressive Orthotopic Mouse Model of Colon Cancer.
Article in Neoplasia (New York, N.Y.), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers, 1 of them a synthesis that pooled it.
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Who cites it
63 citing papers in PubMed, 1 synthesis or guideline pooled it, 102 citations in OpenAlex.
- Cabozantinib in combination with immune checkpoint inhibitors for renal cell carcinoma: a systematic review and meta-analysis.Frontiers in pharmacology · 2024Pooled it
- Review
- CEUS with VEGFR2-targeted microbubbles for monitoring of early immunotherapy effects in a colorectal cancer model.Cancer imaging : the official publication of the International Cancer Imaging Society · 2026Article
- Heterogeneity of macrophages in PD-1/PD-L1 inhibitor therapy: a single-cell perspective.Cellular & molecular biology letters · 2026Review
- Targeting T cell exhaustion in colorectal cancer: emerging roles of LAG-3, TIM-3, and TIGIT signaling in overcoming immunotherapy resistance.Cell communication and signaling : CCS · 2026Review
- ISM2 as a prognostic biomarker and mediator of immune infiltration in colorectal cancer: evidence from bioinformatics and experimental analysis.Journal of gastrointestinal oncology · 2025Article
- Molecular Subtypes and Risk Prediction Model Based on Malignant Cell Differentiation Trajectories in Breast Cancer.Journal of cellular and molecular medicine · 2025Article
- Establishment of an Orthotopic and Metastatic Colorectal Cancer Mouse Model Using a Tissue Adhesive-Based Implantation Method.Cancers · 2025Article
- The immunosurveillance signature predicts the prognosis and immunotherapy sensitivity for colon adenocarcinoma.Scientific reports · 2025Article
- Advances and challenges in CAR-T cell therapy for head and neck squamous cell carcinoma.Biomarker research · 2025Review
- A Mitochondria-Targeted Biomimetic Nanomedicine Capable of Reversing Drug Resistance in Colorectal Cancer Through Mitochondrial Dysfunction.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Strategies to Overcome PD-1/PD-L1 Blockade Resistance: Focusing on Combination with Immune Checkpoint Blockades.Journal of Cancer · 2025Review
- Impact of gut microbiota and its metabolites on immunometabolism in colorectal cancer.Immunometabolism (Cobham, Surrey) · 2024Review
- Article
- Combination of proton- or X-irradiation with anti-PDL1 immunotherapy in two murine oral cancers.Scientific reports · 2024Article
- Role of T cells in liver metastasis.Cell death & disease · 2024Review
- Strategies for Overcoming Immune Evasion in Bladder Cancer.International journal of molecular sciences · 2024Review
- DOCK4 is a Novel Prognostic Biomarker and Correlated with Immune Infiltrates in Colon Adenocarcinoma.Combinatorial chemistry & high throughput screening · 2024Article
- Biological Roles and Clinical Therapeutic Applications of Tumor-Associated Macrophages in Colorectal Liver Metastasis.Journal of inflammation research · 2024Review
- SHR-8068 combined with adebrelimab and bevacizumab in the treatment of refractory advanced colorectal cancer: study protocol for a single-arm, phase Ib/II study.Frontiers in immunology · 2024Article
3 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Immune checkpoint inhibitors have shown clinical benefit in several cancer entities including metastatic microsatellite instable colorectal carcinomas. However, for the majority of metastatic colorectal carcinomas the potential and limitations of immune checkpoint inhibition is not fully understood. In this study, the effects of sole and dual CTLA-4 and PD-L1 blockade were investigated in a microsatellite stable highly aggressive orthotopic mouse model of colon cancer. Dual CTLA-4 and PD-L1 inhibition resulted in tumor growth stagnation and completely blocked liver metastasis. Sole CTLA-4 and PD-L1 inhibition only moderately reduced metastatic spread of the colon cancer cells, though CTLA-4 blockade being superior to PD-L1 inhibition. Dual immune checkpoint blockade and sole CTLA-4 inhibition significantly increased intratumoral CD8+ and CD4+ T cells and reduced FOXP3+/CD4+ Treg cells. This was associated with increased expression levels of the pro-inflammatory Th1/M1-related cytokines IFN-γ, IL-1α, IL-2, and IL-12. Moreover, tumors treated with combined immune checkpoint blockade showed the strongest increase in intratumoral iNOS+ macrophages, reduction of PD-L1+ and Tie2+ macrophages and the lowest expression of M2/Th2-related IL-4, TARC and COX-2. The assessment of further microenvironmental changes by DCE-MRI and immunohistology revealed no alterations in functional tumor vascularization upon combined immune checkpoint blockade, but a significant increase in intratumoral fibroblasts and collagen I deposition. Thus, the synergistic inhibitory effects of dual immune checkpoint inhibition can be explained by anti-tumorigenic T cell responses mediated by CTLA-4 inhibition and M1 macrophage polarization predominantly induced by PD-L1 blockade. This was accompanied by pronounced fibroblast activation highlighting the interconnection between immunogenicity and desmoplasia.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.