Inhibition of CDK4/6 Promotes CD8 T-cell Memory Formation
| العنوان: | Inhibition of CDK4/6 Promotes CD8 T-cell Memory Formation |
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| المؤلفون: | Shengbao Suo, Adrienne M. Luoma, Nathanael S. Gray, Julia McCreary, Sara M. Tolaney, Kelly Boelaars, Max Heckler, Eleanor Clancy-Thompson, Kai W. Wucherpfennig, Guo-Cheng Yuan, Tamara Boschert, Thorsten R. Mempel, Michael Dougan, Stephanie K. Dougan, Kevin Roehle, Lestat R. Ali, Henry W. Long, Patrick J Lenehan, Shom Goel, Vera Peters, Li Qiang, Francesco Marangoni, Katherine S. Ventre, Eric S. Wang |
| المصدر: | Cancer discovery, vol 11, iss 10 Cancer Discov |
| بيانات النشر: | American Association for Cancer Research (AACR), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, Adult, Pyridines, T cell, Oncology and Carcinogenesis, Cell, Aminopyridines, Breast Neoplasms, CD8-Positive T-Lymphocytes, Palbociclib, Inbred C57BL, Article, Piperazines, Breast Neoplasms, Male, Cell Line, Mice, Cell Line, Tumor, Breast Cancer, medicine, Animals, Humans, Gene silencing, Cytotoxic T cell, Protein Kinase Inhibitors, Aged, Cancer, Tumor, Chemistry, T-cell receptor, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Middle Aged, medicine.disease, Mice, Inbred C57BL, medicine.anatomical_structure, Oncology, 5.1 Pharmaceuticals, Cancer research, Benzimidazoles, Female, Development of treatments and therapeutic interventions, CD8 |
| الوصف: | CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies. We examined CDK4/6 inhibition in mouse and human CD8+ T cells during early stages of activation. Mice receiving tumor-specific CD8+ T cells treated with CDK4/6 inhibitors displayed increased T-cell persistence and immunologic memory. CDK4/6 inhibition upregulated MXD4, a negative regulator of MYC, in both mouse and human CD8+ T cells. Silencing of Mxd4 or Myc in mouse CD8+ T cells demonstrated the importance of this axis for memory formation. We used single-cell transcriptional profiling and T-cell receptor clonotype tracking to evaluate recently activated human CD8+ T cells in patients with breast cancer before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8+ memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in patients with cancer may augment long-term protective immunity. Significance: CDK4/6 inhibition skews newly activated CD8+ T cells toward a memory phenotype in mice and humans with breast cancer. CDK4/6 inhibitors may have broad utility outside breast cancer, particularly in the neoadjuvant setting to augment CD8+ T-cell priming to tumor antigens prior to dosing with checkpoint blockade. This article is highlighted in the In This Issue feature, p. 2355 |
| وصف الملف: | application/pdf |
| تدمد: | 2159-8290 2159-8274 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::764cc8feac27854a89e0549eeafb9ff4Test https://doi.org/10.1158/2159-8290.cd-20-1540Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....764cc8feac27854a89e0549eeafb9ff4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21598290 21598274 |
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