CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory
Autor: | Matteo Costacurta, Edwin D. Hawkins, Ricky W. Johnstone, Grant A. McArthur, Jane Oliaro, Paul J Neeson, Paul A. Beavis, Stephin J. Vervoort, Joe Jiang Zhu, Deborah Meyran, Conor J. Kearney, Emily J. Lelliott, Ian A. Parish, Pilar M. Dominguez, Laura Kirby, Nicole M. Haynes, Lydia Lim, Luciano G. Martelotto, Kelly M Ramsbottom, Magnus Zethoven, Isabella Y. Kong, Karen E. Sheppard, Jarrod J. Sandow, Izabela Todorovski |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Pyridines medicine.medical_treatment T cell Antineoplastic Agents Breast Neoplasms Piperazines Memory T Cells Mice 03 medical and health sciences 0302 clinical medicine Immunity Cell Line Tumor PD-L1 medicine Animals Humans Protein Kinase Inhibitors biology business.industry Cyclin-Dependent Kinase 4 Cancer Cyclin-Dependent Kinase 6 Immunotherapy medicine.disease Xenograft Model Antitumor Assays Immune checkpoint Chimeric antigen receptor 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Female CDK4/6 Inhibition business |
Zdroj: | Cancer Discovery. 11:2582-2601 |
ISSN: | 2159-8290 2159-8274 |
Popis: | Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor–positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, whereas their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic, and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunologic T-cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous antitumor T-cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor T cells, and induced a retinoblastoma-dependent T-cell phenotype supportive of favorable responses to immune checkpoint blockade in patients with melanoma. Together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost antitumor T-cell immunity. Significance: Immunologic memory is critical for sustained antitumor immunity. Our discovery that CDK4/6 inhibitors drive T-cell memory fate commitment sheds new light on their clinical activity, which is essential for the design of clinical trial protocols incorporating these agents, particularly in combination with immunotherapy, for the treatment of cancer. This article is highlighted in the In This Issue feature, p. 2355 |
Databáze: | OpenAIRE |
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