Docetaxel suppresses immunotherapy efficacy of natural killer cells toward castration‐resistant prostate cancer cells via altering androgen receptor‐lectin‐like transcript 1 signals

Abstract

Background: Docetaxel is an effective first-line chemotherapy agent used in the treatment of castration-resistant prostate cancer (CRPC) patients. However, most times chemotherapy with docetaxel eventually fails due to the development of docetaxel resistance. Natural killer (NK) cells are the first line of defense against cancer and infections. NK cell function is determined by a delicate balance between signals received via activating and inhibitory receptors. The aim of this study is to explore whether the potential docetaxel-resistant mechanism is associated with impaired NK cell cytotoxicity toward CRPC cells.Methods: By performing MTT assay, we explored the role of docetaxel in regulating NK cells' cytotoxicity. Western blot and quantitative real-time polymerase chain reaction analysis were used to measure messenger RNA and protein levels separately. Luciferase reporter assay and chromatin immunoprecipitation assay were performed to analyze the mechanism.Results: We found that docetaxel could suppress the immunotherapy efficacy of NK cells toward CRPC cells via the androgen receptor (AR)-lectin-like transcript 1 (LLT1) signals in vitro. Analysis of the mechanism revealed that docetaxel functioned through increasing AR to upregulate LLT1 expression in CRPC cells. AR transcriptionally activated LLT1 expression by binding to its promoter region. Furthermore, targeting AR with ASC-J9 or blocking LL1 by anti-human LLT1 monoclonal antibody could reverse the suppressive effect of docetaxel on the immunotherapy efficacy of NK cells toward CRPC cells. Conclusions:We concluded that chemotherapy agent docetaxel could increase AR that transcriptionally regulated the expression of NK inhibitory ligand LLT1 on CRPC cells. An increase of LL1 may further suppress the immunological efficacy of NK cells to kill CRPC cells. Additionally, targeting AR or blocking LL1 could enhance the immunotherapy efficacy of NK cells toward CRPC cells which might be Min Tang, Shenglin Gao, and Lei Zhang contributed equally to this study.

The immune microenvironment and relation to outcome in patients with advanced breast cancer treated with docetaxel with or without gemcitabine

“…53 An inhibitory effect on natural killer cells by docetaxel has also been shown. 54 One possible explanation for our inability to identify a benefit from gemcitabine in tumors with CD8 high expression is that cotreatment with docetaxel may have canceled out any immune stimulatory effects.…”

Identification of a Prognosis-Related Risk Signature for Bladder Cancer to Predict Survival and Immune Landscapes

“…Mathew et al suggested that CLEC2D might allow prostate cancer cells to evade the immune system by inhibiting natural killer cells [ 48 ]. Tang et al suggested that CLEC2D can enhance prostate cancer resistance to docetaxel [ 49 ].…”

The Role of Androgen Receptor in Cross Talk Between Stromal Cells and Prostate Cancer Epithelial Cells

“…By using the coculture system, Galustian et al confirmed that PCa cells had a stronger ability to enhance IL-15-mediated expansion and cytotoxicity of NK cells than non-cancerous cell lines (PNT2 and WPMY-1) (Sakellariou et al, 2020), suggesting that the human body applies a protective strategy against PCa by activating NK cells. Accordantly, another study showed that AR could transcriptionally regulate the expression of NK inhibitory ligand LLT1 (lectin-like transcript 1) in PCa cells (Tang et al, 2020). Castration led to a short decline of AR activity so that the LLT1 level was reduced, eventually contributing to the expansion and activation of NK cells.…”