The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
Immune-Based Antitumor Effects of BRAF Inhibitors Rely on Signaling by CD40L and IFNγ
Open accessPublished version of a preprint
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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1 retracted
Host immunity contributes to the anti-melanoma activity of BRAF inhibitors
Knight, D. A., Ngiow, S. F., Li, M., Parmenter, T. J., Mok, S., Cass, A. A., Haynes, N. M., Kinross, K. M., Yagita∥, H., Koya, R. C., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66236 · Cited by 274
RetractedExploring the full spectrum of macrophage activation
Mosser, D. M., & Edwards, J. P. (2008) · Nature Reviews Immunology · doi:10.1038/nri2448 · Cited by 9,144
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Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S.-J., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.09.006 · Cited by 2,103
Self-citationCD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans
Beatty, G. L., Chiorean, E. G., Fishman, M. P., Saboury, B., Teitelbaum, U. R., Sun, W., Huhn, R. D., Song, W., Li, D., Sharp, L. L., et al. (2011) · Science · doi:10.1126/science.1198443 · Cited by 1,706
Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.11.006 · Cited by 1,355
Self-citationMetabolic Regulation of T Lymphocytes
MacIver, N. J., Michalek, R. D., & Rathmell, J. C. (2013) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032712-095956 · Cited by 1,244
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CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors
Wang, H., Franco, F., Tsui, Y.-C., Xie, X., Trefny, M. P., Zappasodi, R., Mohmood, S. R., Fernández-García, J., Tsai, C.-H., Schulze, I., et al. (2020) · Nature Immunology · doi:10.1038/s41590-019-0589-5 · Cited by 694
Self-citationThe multifaceted role of CD4+ T cells in CD8+ T cell memory
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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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