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https://hdl.handle.net/2440/134515
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Type: | Journal article |
Title: | CDK4/6 inhibition promotes antitumor immunity through the induction of T-cell memory |
Author: | Lelliott, E.J. Kong, I.Y. Zethoven, M. Ramsbottom, K.M. Martelotto, L.G. Meyran, D. Zhu, J.J. Costacurta, M. Kirby, L. Sandow, J.J. Lim, L. Dominguez, P.M. Todorovski, I. Haynes, N.M. Beavis, P.A. Neeson, P.J. Hawkins, E.D. McArthur, G.A. Parish, I.A. Johnstone, R.W. et al. |
Citation: | Cancer Discovery, 2021; 11(10):2582-2601 |
Publisher: | American Association for Cancer Research (AACR) |
Issue Date: | 2021 |
ISSN: | 2159-8274 2159-8290 |
Statement of Responsibility: | Emily J. Lelliott, Isabella Y. Kong, Magnus Zethoven, Kelly M. Ramsbottom, Luciano G. Martelotto, Deborah Meyran, Joe Jiang Zhu, Matteo Costacurta, Laura Kirby, Jarrod J. Sandow, Lydia Lim, Pilar M. Dominguez, Izabela Todorovski, Nicole M. Haynes, Paul A. Beavis, Paul J. Neeson, Edwin D. Hawkins, Grant A. McArthur, Ian A. Parish, Ricky W. Johnstone, Jane Oliaro, Karen E. Sheppard, Conor J. Kearney, and Stephin J. Vervoort |
Abstract: | 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. |
Keywords: | Cell Line, Tumor Animals Humans Mice Breast Neoplasms Piperazines Pyridines Antineoplastic Agents Protein Kinase Inhibitors Xenograft Model Antitumor Assays Female Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase 6 Memory T Cells |
Rights: | ©2021 American Association for Cancer Research |
DOI: | 10.1158/2159-8290.CD-20-1554 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1100189 http://purl.org/au-research/grants/nhmrc/1139626 http://purl.org/au-research/grants/nhmrc/1140187 http://purl.org/au-research/grants/nhmrc/GNT1165591 http://purl.org/au-research/grants/nhmrc/454569 http://purl.org/au-research/grants/nhmrc/GNT1178339 http://purl.org/au-research/grants/nhmrc/159488 |
Published version: | http://dx.doi.org/10.1158/2159-8290.cd-20-1554 |
Appears in Collections: | Medicine publications |
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