The Role of CDKs Inhibitors in Cancer Immunotherapy

Introduction

Cell cycle dysregulation is common phenomena found in many cancer types. CDK members are associated with cell division, cell growth and genetic integrity monitoring under normal condition, while overexpression of CDKs promotes the process of malignant transformation. Genomic and chromosomal instability and the activation of many oncogenic pathways induced by deregulated CDKs enable cancer cell survival [1, 2, 3]. CDKs inhibitors have been showed the tumor regressive effects in various preclinical mouse models [4]. However, these observations were explained by direct cell killing effects, such as cell cycle arrest, senescence or apoptotic cell death [5, 6, 7, 8]. Increasing evidences now have revealed its impact on the remodeling of tumor immune microenvironment (TIME) in cancer immunotherapy.

CDKs Inhibitors induce Immunogenic Effects

Inhibition of CDK family members exerts diverse effects on the modulation of tumor immune microenvironment. Immune checkpoint blockades (ICBs) therapy for solid tumors has been widely studied, especially for melanoma. Clinical trials with the treatment of nivolumab and/or ipilimumab for blocking the interaction of PD-1/PD-L1 resulted in longer progression-free and overall survival, indicating the exciting clinical outcome [9, 10]. CDK4/6 inhibitors have been well studied and approved by U.S. Food and Drug Administration (FDA). Synergistic antitumor effect of CDK4/6 inhibitors treatment enhanced the efficacy of anti-PD-1 immunotherapy through destabilization of PD-L1 [11] and type III interferons [12]. Additionally, CDK4/6 inhibitor and motigen-activated protein kinase (MAPK) inhibitor act in combination to provoke NK surveillance through the activation of senescence-associated secretory phenotype [13]. The anti-cancer immune responses are triggered not only by cell cycle regulators (e.g. CDK1,2,4,6,7), but also by transcription regulators (e.g. CDK7,8,9,10-13). By targeting CDK7, CDK blockade converted tumor cells into an immunogenic signature, characterized by three positively regulated pathways, which are Interferon-γ response, Tumor necrosis factor signaling, and Inflammatory response pathways. Numerous pro-inflammatory cytokines and chemokines are of a significant importance to recruit and activate different innate and adaptive immune cells. This anti-tumor effect is capable of being enhanced by anti-PD-1 immunotherapy. CDK9 inhibition sensitized to ICBs via activating IFN-γ pathway [14]. As the latest identified member, CDK20 ablation has also been proved to enhance the therapeutic efficacy of ICBs in a hepatoma preclinical model [15]. Taken together, CDKs inhibitor can provoke a robust T cell or NK cell-mediated or immune surveillance.

Mechanisms of Resistance to CDK Inhibitors

Despite promising clinical benefits, a large population become resistant to combinational therapies of CDK4/6i and antiestrogen drug in treating ER-positive metastasis breast cancer. The genetic alteration is one aspect responsible for resistance to CDKs inhibitors. Activated KRAS has been blamed for the cause of resistance to a combination of MEK/CDK inhibition therapy by using both ORF gain-of-function and CRISPR loss-of-function screens [16]. Acquired RB1 mutations in circulating tumor DNA (ctDNA) becomes detectable after treated with CDK4/6 inhibitor, which leads to loss of Rb function and indicates the occurrence of resistance [17]. Other pathways like PI3K/AKT/mTOR and EMT are activated to limit the long-term efficacy of CDKs inhibitors [18, 19]. Intriguingly, the remodeling of some immune pathways including IFN-a and IFN-γ has been revealed the resistant cancer cell models. The understanding of resistant mechanisms will eventually help to provide a novel therapeutic strategy.

Clinical Trials for CDKs Inhibitors

To date, there are three CDK4/6 inhibitors have been approved by FDA as initial therapy for HR-positive, HER2-negative advanced or metastatic breast cancer, namely abemaciclib (VERZENIO™, Eli Lilly and Company) in 2018, palbociclib (IBRANCE®, Pfizer Inc.) in 2015 and ribociclib (KISQALI, Novartis Pharmaceuticals Corp.) in 2017. Interestingly, some studies showed enthusiastic results even from triple-negative breast cancer [20]. With a successful preclinical application of CDK4/6 inhibitor, several clinical trials on CDK inhibitors have been done and some are still ongoing with the recruitment of cancer patients [21] and there are 175 studies up to date (by searching https://clinicaltrials.gov). Even over 60 studies focus on the new regimen for breast cancer treatment, phase I/ II clinical trials for other cancer types are undergoing, including colorectal cancer, non-small cell lung cancer, Squamous cell cancer, head and neck cancer, prostate cancer and Relapsed Mantle Cell Lymphoma.

Discussion

Nowadays, cancer treatments and studies shift from tumorcentered killing to deciphering the tumor ecosystem complexity, especially in anti-tumor immunogenic effects [22]. CDKs blockade contributes to cancer treatment not only by directly killing tumor cells but also by exerting its impact on cancer immunity, which, in turn, largely improves the clinical benefits. Additionally, Inactivation of CDK12 in advanced prostate cancer showed higher levels of T-cell infiltration and some specific chemokines and corresponding receptors, benefitting from PD-1 inhibitors. This study implicates that loss-of-function CDKs provides a rationale for personalized therapies for genomically defined tumor subtype [23]. To summarize, targeting CDKs is becoming a promising strategy for new combination regimen in clinical application.

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