Cyclin‐dependent kinase inhibitors enhance programmed cell death protein 1 immune checkpoint blockade efficacy in triple‐negative breast cancer by affecting the immune microenvironment

Abstract

BackgroundClinical studies on programmed death‐ligand 1 (PD‐L1) immune checkpoint inhibitors for treating triple‐negative breast cancer (TNBC) have shown unsatisfactory efficacy due to low tumor‐infiltrating lymphocyte (TIL) levels. Inhibitors targeting cyclin‐dependent kinase (CDK) proteins can affect the immune microenvironment, increase TIL levels, and promote antitumor immunity, thus providing a new direction for TNBC treatment strategies.MethodsThe authors tested three CDK inhibitors on the TNBC cell lines MDA‐MB‐231 and 4T1 and validated their antitumor effects and impact on the immune microenvironment using multiple detection methods. They verified the efficacy and immune‐related mechanisms of different combination therapy experiments in a 4T1 cell‐transplanted BALB/c mouse model.ResultsTreatment with CDK inhibitors for 72 hours inhibited cell proliferation, clone formation, migration, and cell‐cycle arrest and induced apoptosis in human breast cancer MDA‐MB‐231 cells and mouse breast cancer 4T1 cells. CDK inhibitors suppressed DNA methylation by downregulating DNMT1, DNMT3a, and DNMT3b expression. These three inhibitors promoted the secretion of various chemokines, enhanced tumor cell antigen presentation, and increased PD‐L1 expression. CDK inhibitors improved the efficacy of immunotherapy in animal models and increased TIL levels.ConclusionsCombination therapy with CDK and PD‐L1 immune checkpoint inhibitors affects the immune microenvironment, promotes antitumor immunity, and improves the efficacy of immunotherapy for TNBC.

Breast cancer therapy in China: Introducing the Special Collection

“…The objective of this special issue of Cancer is to present recent research progress and related reviews in the field of breast cancer. It mainly focuses on the evaluation of the personalized breast cancer screening scheme, 1 antihuman epidermal growth factor receptor 2 (HER2) antibody-drug conjugate (ADC) drugs, 2,3 low HER2 expression, 3 real-world research on the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and its drug-resistance mechanism, 4 breast cancer immunotherapy (antiprogrammed cell death protein 1 [anti-PD-1] antibodies, 5 chimeric antigen receptor T-cell therapy, 6 etc. ), triplenegative breast cancer (TNBC), 5,[7][8][9] and new adjuvant treatments, 8,10 and it includes several articles describing basic and clinical research on TNBC.…”

“…Four studies on TNBC were conducted during this period, namely: Type I PRMT inhibition primes anti-PD-1 immunotherapy in TNBC, 7 ACTL6A as a potential biomarker for predicting prognosis and neoadjuvant therapy response in TNBC, 8 ; Artificial intelligence-based comprehensive analysis of tertiary lymphoid structure-tumor budding profile to predict the survival of patients with TNBC, 9 and CDK inhibitors enhancing the efficacy of PD-1 immune checkpoint blockade in TNBC by affecting the immune microenvironment. 5 The treatment strategy after the failure of first-line CDK4/6 inhibitors has become a hot topic in clinical practice. Chemotherapy, continuation of another type of CDK4/6 inhibitor, other combination endocrine therapies, and ADC drugs are all strategies; however, there is no consensus about which is best.…”