دورية أكاديمية
أعرض في EDS

MCL1 inhibition targets Myeloid Derived Suppressors Cells, promotes antitumor immunity and enhances the efficacy of immune checkpoint blockade.

التفاصيل البيبلوغرافية
العنوان: MCL1 inhibition targets Myeloid Derived Suppressors Cells, promotes antitumor immunity and enhances the efficacy of immune checkpoint blockade.
المؤلفون: Mukherjee N; University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, 80045, USA., Katsnelson E; University of Colorado Anschutz Medical Campus, School of Medicine, Division of Surgical Oncology, Aurora, CO, 80045, USA., Brunetti TM; Department of Immunology & Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Michel K; University of Colorado Anschutz Medical Campus, School of Medicine, Division of Medical Oncology, Aurora, CO, 80045, USA., Couts KL; University of Colorado Anschutz Medical Campus, School of Medicine, Division of Medical Oncology, Aurora, CO, 80045, USA., Lambert KA; University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, 80045, USA., Robinson WA; University of Colorado Anschutz Medical Campus, School of Medicine, Division of Medical Oncology, Aurora, CO, 80045, USA., McCarter MD; University of Colorado Anschutz Medical Campus, School of Medicine, Division of Surgical Oncology, Aurora, CO, 80045, USA., Norris DA; University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, 80045, USA.; Department of Veterans Affairs Medical Center, Dermatology Section, Denver, CO, 80220, USA., Tobin RP; University of Colorado Anschutz Medical Campus, School of Medicine, Division of Surgical Oncology, Aurora, CO, 80045, USA. Richard.Tobin@cuanschutz.edu., Shellman YG; University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO, 80045, USA. Yiqun.shellman@CUAnschutz.edu.; University of Colorado Anschutz Medical Campus, Gates Center for Regenerative Medicine, Aurora, CO, 80045, USA. Yiqun.shellman@CUAnschutz.edu.
المصدر: Cell death & disease [Cell Death Dis] 2024 Mar 08; Vol. 15 (3), pp. 198. Date of Electronic Publication: 2024 Mar 08.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Pub. Group
مواضيع طبية MeSH: Melanoma*/drug therapy , Skin Neoplasms* , Antineoplastic Agents*/pharmacology , Myeloid-Derived Suppressor Cells*/metabolism, Humans ; Animals ; Mice ; Immune Checkpoint Inhibitors/pharmacology ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; CD8-Positive T-Lymphocytes/metabolism
مستخلص: Immune checkpoint inhibitors (ICIs) are now the first-line treatment for patients with advanced melanoma. Despite promising clinical results, many patients fail to respond to these therapies. BH3 mimetics, a novel class of small molecule inhibitors that bind and inhibit anti-apoptotic members of the BCL2 family proteins such as BCL2 or MCL1, have been very successful in treating hematologic malignancies. However, there are limited studies on the immunomodulatory role of the BH3 mimetics. Several factors contribute to ICI resistance including myeloid-derived suppressor cells (MDSCs) that exert immunosuppressive effects through direct and indirect inhibition of antitumor immunity. Thus, targeting MDSCs to enhance antitumor immunity has the potential to enhance the efficacy of ICIs. In this study, we show that the MCL1 inhibitor S64315 reduces melanoma tumor growth in an immune cell-dependent manner in mice. Specifically, S64315 enhances antitumor immunity by reducing MDSC frequency and by promoting the activity of CD8+T cells. Additionally, human MDSCs are 10 times more sensitive to S64315 than cutaneous melanoma lines. Further, we found that a higher expression of MCL1 is associated with poor survival for patients treated with anti-PD-1. Finally, combining S64315 and anti-PD-1 significantly slowed tumor growth compared to either agent alone. Together, this proof-of-concept study demonstrates the potential of combining an MCL1 inhibitor with anti-PD-1 in the treatment of melanoma. It justifies the further development of next generation MCL1 inhibitors to improve efficacy of ICIs in treating malignant melanoma.
(© 2024. The Author(s).)
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معلومات مُعتمدة: BX000141 Department of Veterans Affairs | James A. Haley Veterans' Hospital (Tampa VA Hospital); R01AR074420 U.S. Department of Health & Human Services | NIH | Center for Information Technology (Center for Information Technology, National Institutes of Health); R01 AR074420 United States AR NIAMS NIH HHS; P30CA046934 Colorado University | Cancer Center, University of Colorado (CU Cancer Center); I01 BX000141 United States BX BLRD VA; P30 CA046934 United States CA NCI NIH HHS
المشرفين على المادة: 0 (Immune Checkpoint Inhibitors)
0 (Myeloid Cell Leukemia Sequence 1 Protein)
0 (Antineoplastic Agents)
0 (MCL1 protein, human)
تواريخ الأحداث: Date Created: 20240308 Date Completed: 20240311 Latest Revision: 20240523
رمز التحديث: 20240523
مُعرف محوري في PubMed: PMC10923779
DOI: 10.1038/s41419-024-06524-w
PMID: 38459020
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-4889
DOI:10.1038/s41419-024-06524-w