Disruption of RBMS3 suppresses PD-L1 and enhances antitumor immune activities and therapeutic effects of auranofin against triple-negative breast cancer

Breast cancer (BC) is the most common malignancy affecting women and the leading cause of cancer-related death worldwide [1]. Triple-negative breast cancer (TNBC) is the most aggressive and lethal form of BC and account for approximately 15–20% of all diagnosed BC cases. TNBC is characterized by the lack of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) [2]. Given limited benefit from endocrine therapies or anti-HER2 therapy, traditional chemotherapy still remains as first-line therapy. Due to inherent complexity and the lack of targeted therapy, TNBC generally presents with a higher rate of metastasis and worse prognosis compared to other subtypes, highlighting a considerable unmed medical need for effective regimens for TNBC [[3], [4], [5]].

Advances in the understanding of tumor biology and the role of tumor-infiltrating lymphocytes (TILs) in BC has resulted in a profusion of clinical research evaluating immunotherapy for treating TNBC. Immune checkpoint blockades (ICBs) targeting the immunosuppressive molecules CTLA-4 and PD-1 (and its ligand, PD-L1) have recently been integrated into the treatment paradigms of multiple traditionally poor-prognosis cancer types [6]. However, the efficacy of ICBs in treating TNBC is still being challenged. The majority of TNBC patients show limited responses and unfavorable prognosis, especially when tumors lack tumor-infiltrating lymphocyts (TILs), failing to stimulate anti-tumor immunity. Aberrant activation of the inhibitory TIL response, known as immune checkpoints, helps cancer cells to evade immune attacks. Cancer cells, by over-expressing immune checkpoint PD-L1 on their surface, engage with cytotoxic T-cells, hindering their functions and circumvent the T cell-mediated immunosurveillance [7]. Increased PD-L1 expression in response to chemotherapy and targeted therapies leads to drug resistance in multiple cancers. While targeting PD-L1/PD1 axis reinvigorate the exhausted TILs in the tumor microenvironment (TME), showing promising values for cancer immunotherapy, the response rates from a monotherapy of ICBs are not quite satisfying [8]. Hence, identification of suitable targets to improve anti-tumor immune activities against TNBC is necessary. More recently, a rationale of combining ICBs with other agents has emerged and remains a topic of investigation [9].

RNA binding proteins (RBPs) participate in almost all steps of post-transcriptional regulation, whose abnormal expression are closely related to the occurrence and development of many cancers [10,11]. To date, the function and mechanisms of RBPs in regulating immunotherapy for TNBC remains largely elusive. RNA binding motif, single-stranded interacting protein 3 (RBMS3) belongs to the small family of c-myc single stranded binding proteins, which contains other members including RBMS1 and RBMS2 [12,13]. RBMS3 was initially identified as binding to an upstream element of the mouse collagen α2 gene promoter and later found to be involved in tumor development through post-transcriptional regulatory mechanisms, including modulation of target mRNA stability [14,15]. Recently, RBMS3 was recognized as a common EMT effector for BC progression via stabilizing EMT transcription factor PRRX1 mRNA stability, and the RBMS3-mediated EMT was necessary to maintain the mesenchymal phenotype and invasion and migration in vitro [16]. While the physiological functions of RBMS3 remain unclear, it can act as either an oncogene or tumor suppressor like other EMT regulatory factors, depending on the tissues-specific context [17].

Here, we identified that RBMS3 is a crucial regulator of PD-L1 in TNBC cells. While ectopic RBMS3 induces PD-L1 expression in MCF-7 cells, depletion of RBMS3 downregulates PD-L1 in MDA-MB231 cells. Mechanistically, RBMS3 drives PD-L1 upregulation by increasing PD-L1 mRNA stability. Rbms3 significantly correlates with immunosuppressive molecules including Rbms1, CD39 and CD73. Auranofin (AUF), an FDA-approved thioredoxin reductase inhibitor, is known to induce a significant anticancer activity in vivo in multiple cancers, including TNBC [[18], [19], [20]]. However, TNBC tumors tend to relapse and develop resistance to AUF after 2-week treatment cycle. Emerging data indicated that AF upregulates PD-L1 levels on TNBC cells via ERK1/2 activation, which then leads to tumor immune evasion and development of AF resistance [21]. Therefore, we investigated the effect of RBMS3 depletion on conquering AUF resistance and enhancing the efficacy of AUF treatment. We found that combinatorial therapy of RBMS3 knockdown and auranofin (AUF) synergistically potentiated the tumor-suppressive effect of AUF on MDA-MB-231 cell migration and invasion in vitro and facilitates anti-tumor T-cell immunity in vivo. In summary, our study reveals RBMS3 as a post-transcriptional regulator of PD-L1 that may contribute to immune escape in TNBC, which could lead to novel combination strategies to enhance the efficacy of cancer immunotherapy.

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