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

Lelliott, Emily J.; Kong, Isabella Y.; Zethoven, Magnus; Ramsbottom, Kelly M.; Martelotto, Luciano G.; Meyran, Déborah; Zhu, Joe Jiang; Costacurta, Matteo; Kirby, Laura; Sandow, Jarrod J.; Lim, Lydia; Domínguez, Pilar M.; Todorovski, Izabela; Haynes, Nicole M.; Beavis, Paul A.; Neeson, Paul J.; Hawkins, Edwin D.; McArthur, Grant A.; Parish, Ian A.; Johnstone, Ricky W.; Oliaro, Jane; Sheppard, Karen E.; Kearney, Conor J.; Vervoort, Stephin J.

doi:10.1158/2159-8290.cd-20-1554

Cited by 75 publications

(59 citation statements)

References 61 publications

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“…The previous success of immunotherapy based on anti-cytotoxic TL-associated antigen 4 or anti-programmed death-1/programmed death ligand-1 antibodies confirms the relevance of TL-based anti-tumor immunity and suggests that restoration of the immune system could promote tumor control (31). Several animal and in vitro models have demonstrated the immune actions of CDK4/6i (32)(33)(34). CDK4/6i increase the immunogenicity of tumor cells (32) and enhance tumor infiltration via TL activation (35,36).…”

Section: Discussionmentioning

confidence: 86%

Baseline lymphopenia as prognostic factor in patients with metastatic breast cancer treated with palbociclib

Emile¹,

Penager

Lévy³

et al. 2021

Oncol Lett

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Section: Discussionmentioning

confidence: 86%

Baseline lymphopenia as prognostic factor in patients with metastatic breast cancer treated with palbociclib

Emile¹,

Penager

Lévy³

et al. 2021

Oncol Lett

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“…Studies in our laboratory have shown encouraging in vivo anti-melanoma activity of palbociclib in combination with BRAF-MEKi [ 15 , 16 ]. Additional pre-clinical studies also demonstrate potential immuno-modulation by CDK4/6 inhibitors (CDK4/6i) in breast cancer and melanoma with upregulation of MHC Class I expression, T regulatory cell reduction, increased IFN-γ release in the tumor microenvironment and enhanced long-term anti-tumor immunity [ 17 , 18 , 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma

Lau

Cullinane

Jackson

et al. 2021

Cancers

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Despite the success of immune checkpoint inhibitors that target cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed-cell-death-1 (PD-1) in the treatment of metastatic melanoma, there is still great need to develop robust options for patients who are refractory to first line immunotherapy. As such there has been a resurgence in interest of adoptive cell transfer (ACT) particularly derived from tumor infiltrating lymphocytes. Moreover, the addition of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) have been shown to greatly extend duration of response in combination with BRAF-MEK inhibitors (BRAF-MEKi) in pre-clinical models of melanoma. We therefore investigated whether combinations of BRAF-MEK-CDK4/6i and ACT were efficacious in murine models of melanoma. Triplet targeted therapy of BRAF-MEK-CDK4/6i with OT-1 ACT led to sustained and robust anti-tumor responses in BRAFi sensitive YOVAL1.1. We also show that BRAF-MEKi but not CDK4/6i enhanced MHC Class I expression in melanoma cell lines in vitro. Paradoxically CDK4/6i in low concentrations of IFN-γ reduced expression of MHC Class I and PD-L1 in YOVAL1.1. Overall, this work provides additional pre-clinical evidence to pursue combination of BRAF-MEK-CDK4/6i and to combine this combination with ACT in the clinic.

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“…However, post expansion phase, cells that have been previously exposed to the inhibitors produce a greater pool of memory T cells by upregulating Max Dimerization Protein (Mxd)4, a negative regulator of Myc/Max formation (Heckler et al, 2021). Interestingly, this event seems to be independent of cell cycle arrest, suggesting a role for CDK4/6 in affecting T cell development (Heckler et al, 2021;Lelliott et al, 2021).…”

Section: Expansion Phase (Il-2 Driven Proliferation)mentioning

confidence: 99%

“…There is a 3-fold increase in cyclin D2, and 8-fold increase in cyclin D3, and around a 30-fold increase in CDK4/6 copies, while p27 decreases 19-fold. Interestingly, CD8 + T cells can bypass CDK4/6 inhibition (Goel et al, 2017), leading to slowed proliferation (Heckler et al, 2021;Lelliott et al, 2021), but not arrest. The major changes observed copies in the Rb-E2F pathway may contribute to this resistance to G1 arrest by CDK4/6 inhibitors.…”

Section: The Cell Cycle Control Protein Network In T Cellsmentioning

confidence: 99%

Cell Cycle Entry Control in Naïve and Memory CD8+ T Cells

Lewis

2021

Front. Cell Dev. Biol.

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CD8+ T cells play important roles in immunity and immuno-oncology. Upon antigen recognition and co-stimulation, naïve CD8+ T cells escape from dormancy to engage in a complex programme of cellular growth, cell cycle entry and differentiation, resulting in rapid proliferation cycles that has the net effect of producing clonally expanded, antigen-specific cytotoxic T lymphocytes (CTLs). A fraction of activated T cells will re-enter dormancy by differentiating into memory T cells, which have essential roles in adaptive immunity. In this review, we discuss the current understanding of cell cycle entry control in CD8+ T cells and crosstalk between these mechanisms and pathways regulating immunological phenotypes.

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

Abstract: The Johnstone laboratory receives research support from Roche, BMS, Astra-Zeneca and MecRx. RWJ is a scientific consultant and shareholder in MecRx. The McArthur laboratory receives non-financial support from Pfizer Oncology for supply of palbociclib.Research.

Cited by 75 publications

References 61 publications

Baseline lymphopenia as prognostic factor in patients with metastatic breast cancer treated with palbociclib

Baseline lymphopenia as prognostic factor in patients with metastatic breast cancer treated with palbociclib

Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma

Cell Cycle Entry Control in Naïve and Memory CD8+ T Cells

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