Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have well-defined tumour-intrinsic cytostatic mechanisms. They are an approved treatment for hormone receptor–positive breast cancer and currently under evaluation in numerous clinical trials for other cancer types.
Less well understood is an emerging immunomodulatory role for CDK4/6 inhibitors (CDK4/6i) in promoting antitumour immunity, where sustained immunologic memory is critical and T-cell dysfunction in the tumour microenvironment is a major barrier. Both tumour-intrinsic mechanisms (such as increasing expression of MHC class I) and direct effects on the immune system, such as enhancing T-cell activation, are attributed to CDK4/6i.
Here Lelliott et al. demonstrate a novel action of CDK4/6i in promoting phenotypic and functional acquisition of T-cell memory, identifying CDK4/6 as a critical regulator of T-cell memory fate commitment.
Performing global phosphoproteomics to determine the molecular drivers involved, they use a Bruker timsTOF Pro and IonOpticks Aurora Series columns to map the global phosphorylation changes that occurs following inhibition of CDK4/6 kinase activity, showing significant loss of specific phosphorylation sites on multiple peptides, including canonical CDK4/6 targets.
This discovery sheds new light on the clinical activity of CDK4/6 inhibitors and will be essential for the design of clinical trial protocols incorporating these agents (particularly in combination with immunotherapy) for the treatment of cancer. Further, it broadens the prospective utility of CDK4/6i as tools to boost antitumour T-cell immunity.
Read the full paper
CDK4/6 inhibition promotes anti-tumor immunity through the induction of T cell memory.
Cancer Discovery 2021; 11(10): 2582–601, October 1, 2021. doi: 10.1158/2159-8290.CD-20-1554
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
Commentary by Jarrod Sandow, PhD.
About the author
Jarrod has a background in biotechnology and completed his PhD at the Institute of Medical and Veterinary Science in Adelaide. He is a co-inventor of IonOpticks’ core technology and is driven towards developing innovative solutions for the global proteomics research community that will enable scientists and clinicians to discover more from their samples to accelerate advances in biological and medical research.