CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory

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; Stephin J Vervoort

Journal article

CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory

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 Show all

CANCER DISCOVERY | AMER ASSOC CANCER RESEARCH | Published : 2021

DOI: 10.1158/2159-8290.CD-20-1554

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 endog..

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University of Melbourne Researchers

Ian Parish Author The Sir Peter Maccallum Department of Oncology

Grant McArthur Author Melbourne Medical School

Conor Kearney Author The Sir Peter Maccallum Department of Oncology

Stephanus Vervoort Author The Sir Peter Maccallum Department of Oncology

Joe Zhu Author The Sir Peter Maccallum Department of Oncology

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Grants

Awarded by National Health and Medical Research Council

Awarded by National Breast Cancer Foundation

Awarded by CASS Foundation Medicine/Science Grant

Awarded by NWO

Awarded by Melbourne University Research Scholarship

Awarded by Leukemia & Lymphoma Society

Funding Acknowledgements

This work was supported by the National Health and Medical Research Council project grants [1100189 (to G.A. McArthur and K.E. Sheppard); 1139626 (to J. Oliaro and R.W. Johnstone); and 1140187 and 1165591 (to E.D. Hawkins)], program grants (454569, to R.W. Johnstone and P.J. Neeson), and fellowships [EL1, GNT1178339, to S.J. Vervoort; 159488, to C.J. Kearney (ECF); R.W. Johnstone (SPRF); to E.D. Hawkins (CDF2)]; Peter Mac Foundation grant (to S.J. Vervoort); Cancer Council Victoria project grants (to R.W. Johnstone); National Breast Cancer Foundation grants (IIRS-18-151, to J. Oliaro) and fellowships (ECF-17-005, to P.A. Beavis); The CASS Foundation Medicine/Science Grant (9870, to E.J. Lelliott); Netherlands Organization for Scientific Research (Rubicon Fellowship, NWO, 019.161LW.017, to S.J. Vervoort); PeterMac Postgraduate Scholarship (to E.J. Lelliott); Melbourne University Research Scholarship (58616, to E.J. Lelliott); Cancer Therapeutics CRC (CTx) PhD Top Up Scholarship (to E.J. Lelliott); The Kids' Cancer Project (to R.W. Johnstone and S.J. Vervoort); Leukemia & Lymphoma Society grant (6552-18, to E.D. Hawkins); Plan Cancer 2014-2019, l'Institut Servier and Fondation Nuovo-Soldati (to D. Meyran) and Pfizer Oncology. We thank Shahneen Sandhu and the Peter MacCallum Cancer Centre Melanoma Biomarker Project for provision of patient samples, and the Peter MacCallum Cancer Centre Translation Research Laboratory (Carleen Cullinane, Susan Jackson, Kerry Warren, and Jeannette Schreuders) for technical support with animal work.