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Immune-Based Antitumor Effects of BRAF Inhibitors Rely on Signaling by CD40L and IFNγ
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Abstract
B-RafV600E inhibitors have been suggested to promote tumor regression with the help of host immunity, but this hypothesis has not been examined directly in detail. In this study, we profiled immunologic changes in the tumor microenvironment and tumor-infiltrating lymphocytes (TIL) in a B-RafV600E/Pten-driven murine model of melanoma after administration of the B-RafV600E small molecule inhibitor PLX4720. In this model, we found that as tumors developed, they gradually acquired immunosuppressive features, including accumulation of regulatory T cells (Treg) and CD11b+/Gr-1+ myeloid cells and loss of Th1 effector functions on CD4+ TILs, such as CD40L and IFNγ expression. PLX4720 administration promoted development of a more immune stimulatory microenvironment associated with a relative increase in CD40L and IFNγ expression on intratumoral CD4+ TILs and a reduced accumulation of Tregs and CD11b+/Gr-1+ myeloid cells. Strikingly, CD40L or IFNγ blockade compromised the ability of PLX4720 to inhibit melanoma growth. Supporting this result, agonistic CD40 antibody was sufficient to evoke antitumor immunity and suppress tumor growth in tumor-bearing mice. Taken together, our results establish the critical role of immune-related changes, with key contributions for CD40L and IFNγ signaling in the antitumor responses triggered in vivo by B-RafV600E inhibitors. Cancer Res; 74(12); 3205–17. ©2014 AACR.
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“We used a subcutaneously engrafted BRAFV600E melanoma model, which is clinically relevant and ICI-resistant23,24.”
From Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy (2025) · cites this paper as [23]
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Metadata
- Authors
- Ho, P.-C., Meeth, K. M., Tsui, Y.-C., Srivastava, B., Bosenberg, M. W., & Kaech, S. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Kaech, Susan M.
- Venue
- Cancer Research
- Published
- 2014-06-12
- Volume
- 74
- Issue
- 12
- Pages
- 3205-3217
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4063281
- OpenAlex
- W1974056979
- Cited by
- 126
- References
- 53
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 4 · 2023: 16 · 2022: 15 · 2021: 15 · 2020: 19 · 2019: 10 · 2018: 4 · 2017: 7 · 2016: 9 · 2015: 12 · 2014: 5
- FWCI
- 5.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Yale University
- National Cancer Institute (P50CA121974, P30CA016359)
- National Institute of Allergy and Infectious Diseases (R01AI074699)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- BRAF V600E inhibitors, PLX4720, melanoma, tumor microenvironment, tumor-infiltrating lymphocytes, CD40 ligand, interferon-gamma, regulatory T cells, myeloid cells, antitumor immunity, immune checkpoint blockade, PTEN
- MeSH terms
- Animals, Antigen-Presenting Cells, Antineoplastic Agents, Drug Screening Assays, Antitumor, Indoles, Interferon-gamma, Macrophages, Melanoma, Experimental, Mice, Transgenic, Skin Neoplasms, Sulfonamides, Signal Transduction, CD4-Positive T-Lymphocytes, Mutation, Missense, CD40 Ligand, Proto-Oncogene Proteins B-raf, Mice, Tumor Microenvironment
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