Inhibition of CDK4/6 Promotes CD8 T-cell Memory Formation

Abstract

CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies.We examined CDK4/6 inhibition in mouse and human CD8 T cells during early stages of activation. Mice receiving tumor-specific CD8 T cells treated with CDK4/6 inhibitors displayed increased T cell persistence and immunologic memory. CDK4/6 inhibition upregulated Mxd4, a negative regulator of Myc, in both mouse and human CD8 T cells. Silencing of Mxd4 or Myc in mouse CD8 T cells demonstrated the importance of this axis for memory formation. We used single cell transcriptional profiling and TCR clonotype tracking to evaluate recently activated human CD8 T cells in breast cancer patients before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8 memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in cancer patients may augment long-term protective immunity.

MYC deficiency impairs the development of effector/memory T lymphocytes

“…Moreover, it was previously reported that the amount of MYC protein is greater in CD8 + than in CD4 + T lymphocytes (Marchingo et al, 2020), suggesting that CD8 + T cells would be more sensitive to Myc deletion. Conversely to our result, a recent study (Heckler et al, 2021) shows that MYC inhibition (using Palbociclib, a CDK4/6 inhibitor) promotes CD8 T cell memory formation. This contrasting observation can be explained by the fact that in Heckler et al paper only the MYC-MAX function is affected, thus some MYC functions independent of MAX, such as the transcription of RNA polymerase III targets, are not impacted (van Riggelen et al, 2010).…”

Cellular mechanisms underlying response and resistance to CDK4/6 inhibitors in the treatment of hormone receptor-positive breast cancer

“…This is attributable, at least in part, to inhibition of CDK6-mediated phosphorylation of nuclear factor of activated T cells (NFAT) transcription factors [ 78 , 81 ]. Most recently, CDK4/6i has also been demonstrated to promote differentiation of CD8 T cells toward a memory cell fate, which might contribute to enhanced anti-tumor efficacy [ 83 , 84 ]. Data on whether this memory differentiation effect in CD8 T cells is RB-dependent are mixed.…”

Molecular Characteristics, Oncogenic Roles, and Relevant Immune and Pharmacogenomic Features of EVA1B in Colorectal Cancer

“…It triggers tumor inhibition through regulation of ULF-dependent p19Arf ubiquitylation ( 47 ). CDK4/6 inhibitor upregulates MXD4 expression that negatively modulates MYC in CD8+ T cells ( 48 ). NR1H2 modulates cholesterol homeostasis within human cells, controlling fitness and function of activated T cells ( 49 ).…”