CDK4/6 inhibition promotes anti-tumor immunity through the induction of T cell memory
- Lelliott, EJ; Kong, IY; Zethoven, M; Ramsbottom, KM; Martelotto, LG; Meyran, D; Jiang Zhu, J; Costacurta, M; Kirby, L; Sandow, JJ; Lim, L; Dominguez, PM; Todorovski, I; Haynes, NM; Beavis, PA; Neeson, PJ; Hawkins, ED; McArthur, GA; Parish, IA; Johnstone, RW; Oliaro, J; Sheppard, KE; Kearney, CJ; Vervoort, SJ;
- Journal Title
- Cancer Discovery
- Publication Type
- epub ahead of print
- Pharmacological 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, while 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 immunological T cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous anti-tumor T cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor (CAR)-T cells, and induced an RB-dependent T cell phenotype supportive of favorable responses to immune checkpoint blockade in melanoma patients. Together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost anti-tumor T cell immunity.
- WEHI Research Division(s)
- Immunology; Advanced Technology And Biology
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2021-05-17 11:04:13Last Modified: 2021-05-17 11:48:12