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NDRG2 Expression in Breast Cancer Cells Downregulates PD-L1 Expression and Restores T Cell Proliferation in Tumor-Coculture

乳腺癌細(xì)胞中的 NDRG2 表達(dá)下調(diào) PD-L1 表達(dá)并恢復(fù)腫瘤共培養(yǎng)中的 T 細(xì)胞增殖

N-myc downstream-regulated gene 2 (NDRG2) is a candidate tumor suppressor in various cancers, including breast cancer. Increased expression of programmed death ligand 1 (PD-L1) is frequently observed in human cancers. Despite its role in cancer cells, the effects of NDRG2 on PD-L1 expression and PD-L1-PD-1 pathway disruption have not been investigated. We demonstrated that NDRG2 overexpression inhibits PD-L1 expression in human breast cancer cells. Blocking T cell proliferation by coculture with 4T1 mouse tumor cells that express high levels of PD-L1 could be significantly reversed by NDRG2 overexpression in the same tumor cells. NDRG2 knockdown in NDRG2-transfected cells elicited the upregulation of PD-L1 expression and accelerated the inhibition of T cell proliferation. These findings were confirmed from The Cancer Genome Atlas (TCGA) data that PD-L1 expression in basal and triple-negative breast cancer (TNBC) patients, but not in luminal A or B cancer patients, was negatively correlated with the NDRG2 expression.

N-myc 下游調(diào)節(jié)基因 2 (NDRG2) 是各種癌癥（包括乳腺癌）中的候選腫瘤抑制因子。在人類癌癥中經(jīng)常觀察到程序性死亡配體 1 (PD-L1) 的表達(dá)增加。盡管 NDRG2 在癌細(xì)胞中發(fā)揮作用，但尚未研究 NDRG2 對(duì) PD-L1 表達(dá)和 PD-L1-PD-1 通路破壞的影響。我們證明了 NDRG2 過表達(dá)抑制人乳腺癌細(xì)胞中 PD-L1 的表達(dá)。通過與表達(dá)高水平 PD-L1 的 4T1 小鼠腫瘤細(xì)胞共培養(yǎng)阻斷 T 細(xì)胞增殖，可以通過在相同腫瘤細(xì)胞中過表達(dá) NDRG2 顯著逆轉(zhuǎn)。NDRG2 轉(zhuǎn)染細(xì)胞中的 NDRG2 敲低引起 PD-L1 表達(dá)上調(diào)并加速抑制 T 細(xì)胞增殖。

高效搖瓶

Programmed cell death protein 1, also known as CD279, is one of the multiple co-inhibitory molecules expressed on the surface of immune-related lymphocytes, such as activated T cells, B cells, and myeloid cells. It binds to two ligands, PD-L1 (CD274) and PD-L2 (CD273), on cancer cells or immune infiltrates [1]. Interestingly, although PD-L2 also contributes to PD-1-mediated T cell inhibition and has a stronger affinity for PD-1 than does PD-L1, antibodies against PD-1, which are able to block binding to both PD-L1 and PD-L2, do not exhibit higher clinical efficacy than antibodies against PD-L1. Thus, in the human tumor microenvironment (TME), PD-L1 is widely believed to be the dominant inhibitory ligand of PD-1 on T cells. Interaction of PD-1 with PD-L1 can affect the activity of T cells in diverse ways, such as by suppressing cytokine production, T cell proliferation, survival, and other effector T cell functions. Therefore, an improved understanding of the mechanisms that regulate PD-L1 expression in tumor cells could lead to better clinical outcomes [2,3]. The effects of checkpoint signaling through PD-1 are reasonably well understood, whereas reverse signaling through PD-L1 within cancer cells has been investigated less than checkpoint signaling through PD-1. Although there are no canonical signaling motifs in cytoplasmic tail of PD-L1, recent literature has implicated the intracellular domain of PD-L1 for evasion of cancer cells from various apoptotic stimuli and its intrinsic signaling properties [4]. For instance, cancer cells with upregulated PD-L1 expression can protect tumor cells from cytotoxic T lymphocyte (CTL)-mediated cytolysis and from the cytotoxic effects of type 1 and type II interferons through reverse PD-L1 signaling within cancer cells, without PD-1 signaling in T cells.

N-myc downstream-regulated gene 2 (NDRG2), a member of the NDRG family, was identified as a stress-responsive gene whose expression is not only downregulated by N-myc gene expression, but also transcriptionally activated by several types of cellular stress stimuli. It has been reported in mammals that there are four types of NDRGs, such as NDRG1, 2, 3, and 4, which all have 57–65% identical amino acid sequences. They have a common NDR domain in the middle of the protein containing an alpha (α)/beta (β) hydrolase-like region [5]. The expression of NDRG2 induced by several stress stimuli, such as hypoxia, DNA damage or endoplasmic reticulum stress (ERS), and other pathological conditions is often associated with its tumor suppressor function in multiple solid tumors, including breast cancer [6], colorectal cancer [7], renal cell carcinoma [8], and lung cancer [9]. It has been also demonstrated that NDRG2 is an important repressor of the PI3K/AKT and NF-κB signaling pathways, which have critical functions in cell proliferation. In particular, our previous study has shown that NDRG2 expression can inhibit breast cancer development by inhibiting tumor cell proliferation, migration, and epithelial-mesenchymal transition (EMT) [10].

Despite the accumulated evidence indicating a tumor suppressive role of NDRG2 in various types of tumors, the question of whether the interaction between tumor cells and immune cells can be influenced by NDRG2 expression in tumor cells remains unanswered. In the present study, we sought to investigate whether NDRG2 expression in aggressive breast tumor cells can influence PD-L1 expression, eventually leading to the alteration of T cell proliferation in response to coculture with tumor cells.

三角細(xì)胞搖瓶

程序性細(xì)胞死亡蛋白 1，也稱為 CD279，是免疫相關(guān)淋巴細(xì)胞（如活化的 T 細(xì)胞、B 細(xì)胞和骨髓細(xì)胞）表面表達(dá)的多種共抑制分子之一。它與癌細(xì)胞或免疫浸潤(rùn)物上的兩種配體 PD-L1 (CD274) 和 PD-L2 (CD273) 結(jié)合 [ 1]。有趣的是，雖然 PD-L2 也有助于 PD-1 介導(dǎo)的 T 細(xì)胞抑制，并且對(duì) PD-1 的親和力比 PD-L1 更強(qiáng)，但針對(duì) PD-1 的抗體能夠阻斷與 PD-L1 和PD-L2 的臨床療效不高于針對(duì) PD-L1 的抗體。因此，在人類腫瘤微環(huán)境（TME）中，PD-L1被廣泛認(rèn)為是PD-1對(duì)T細(xì)胞的主要抑制配體。PD-1 與 PD-L1 的相互作用可以以多種方式影響 T 細(xì)胞的活性，例如通過抑制細(xì)胞因子產(chǎn)生、T 細(xì)胞增殖、存活和其他效應(yīng) T 細(xì)胞功能。因此，更好地了解調(diào)節(jié)腫瘤細(xì)胞中 PD-L1 表達(dá)的機(jī)制可能會(huì)帶來(lái)更好的臨床結(jié)果 [ 2 , 3]。通過 PD-1 的檢查點(diǎn)信號(hào)傳導(dǎo)的影響已被很好地理解，而在癌細(xì)胞內(nèi)通過 PD-L1 的反向信號(hào)傳導(dǎo)的研究少于通過 PD-1 的檢查點(diǎn)信號(hào)傳導(dǎo)。盡管 PD-L1 的細(xì)胞質(zhì)尾部沒有典型的信號(hào)基序，但最近的文獻(xiàn)表明 PD-L1 的細(xì)胞內(nèi)結(jié)構(gòu)域可用于逃避各種凋亡刺激的癌細(xì)胞及其固有的信號(hào)傳導(dǎo)特性 [ 4 ]。例如，PD-L1 表達(dá)上調(diào)的癌細(xì)胞可以通過癌細(xì)胞內(nèi)的反向 PD-L1 信號(hào)傳導(dǎo)保護(hù)腫瘤細(xì)胞免受細(xì)胞毒性 T 淋巴細(xì)胞 (CTL) 介導(dǎo)的細(xì)胞溶解和 1 型和 II 型干擾素的細(xì)胞毒性作用，而無(wú)需 PD- 1 T 細(xì)胞中的信號(hào)傳導(dǎo)。

N-myc 下游調(diào)節(jié)基因 2 (NDRG2) 是 NDRG 家族的成員，被鑒定為一種應(yīng)激反應(yīng)基因，其表達(dá)不僅被 N-myc 基因表達(dá)下調(diào)，而且被幾種類型的細(xì)胞應(yīng)激轉(zhuǎn)錄激活刺激。據(jù)報(bào)道，在哺乳動(dòng)物中有四種類型的 NDRG，如 NDRG1、2、3 和 4，它們都具有 57-65% 的相同氨基酸序列。它們?cè)诤?α (α)/β (β) 水解酶樣區(qū)域的蛋白質(zhì)中間有一個(gè)共同的 NDR 結(jié)構(gòu)域 [ 5 ]。NDRG2 在多種應(yīng)激刺激（如缺氧、DNA 損傷或內(nèi)質(zhì)網(wǎng)應(yīng)激 (ERS) 和其他病理?xiàng)l件下）誘導(dǎo)的表達(dá)通常與其在包括乳腺癌在內(nèi)的多種實(shí)體瘤中的抑癌功能有關(guān) [ 6]、結(jié)直腸癌 [ 7 ]、腎細(xì)胞癌 [ 8 ] 和肺癌 [ 9 ]。還證明 NDRG2 是 PI3K/AKT 和 NF-κB 信號(hào)通路的重要阻遏物，在細(xì)胞增殖中具有關(guān)鍵功能。特別是，我們之前的研究表明，NDRG2 的表達(dá)可以通過抑制腫瘤細(xì)胞的增殖、遷移和上皮-間質(zhì)轉(zhuǎn)化 (EMT) [ 10 ]來(lái)抑制乳腺癌的發(fā)展。

盡管積累的證據(jù)表明 NDRG2 在各種類型的腫瘤中具有抑癌作用，但腫瘤細(xì)胞和免疫細(xì)胞之間的相互作用是否會(huì)受到腫瘤細(xì)胞中 NDRG2 表達(dá)的影響的問題仍未得到解答。在本研究中，我們?cè)噲D研究侵襲性乳腺腫瘤細(xì)胞中 NDRG2 的表達(dá)是否會(huì)影響 PD-L1 的表達(dá)，最終導(dǎo)致 T 細(xì)胞增殖改變以響應(yīng)與腫瘤細(xì)胞的共培養(yǎng)。

細(xì)胞培養(yǎng)瓶

In the present study, it was confirmed that downregulation of NDRG2, which is often observed in several types of cancer patients, is associated with upregulation of PD-L1 expression in breast cancer cells and patients. NDRG2 expression in breast cancer cells could restore the T cell proliferation activity that is suppressed by PD-L1 expression on tumor cells.

在本研究中，證實(shí)了在幾種類型的癌癥患者中經(jīng)常觀察到的 NDRG2 的下調(diào)與乳腺癌細(xì)胞和患者中 PD-L1 表達(dá)的上調(diào)有關(guān)。乳腺癌細(xì)胞中 NDRG2 的表達(dá)可以恢復(fù)被腫瘤細(xì)胞上 PD-L1 表達(dá)抑制的 T 細(xì)胞增殖活性。

關(guān)鍵詞： 免疫檢查點(diǎn),PD-L1,NDRG2 ,乳腺癌,T細(xì)胞增殖,TCGA數(shù)據(jù),immune checkpoint,PD-L1; NDRG2; breast cancer,T cell proliferation,TCGA data

來(lái)源：MDPI https://www.mdpi.com/2072-6694/13/23/6112/htm