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Multifaceted Roles of Chemokines and Chemokine Receptors in Tumor Immunity

趨化因子和趨化因子受體在腫瘤免疫中的多方面作用

Various immune cells are involved in host immune responses to cancer. T-helper (Th) 1 cells, cytotoxic CD8+ T cells, and natural killer cells are the major effector cells in anti-tumor immunity, whereas cells such as regulatory T cells and myeloid-derived suppressor cells are negatively involved in anti-tumor immunity. Th2 cells and Th17 cells have been shown to have both pro-tumor and anti-tumor activities. The migratory properties of various immune cells are essential for their function and critically regulated by the chemokine superfamily. In this review, we summarize the roles of various immune cells in tumor immunity and their migratory regulation by the chemokine superfamily. We also assess the therapeutic possibilities of targeting chemokines and chemokine receptors in cancer immunotherapy.

多種免疫細(xì)胞參與宿主對癌癥的免疫反應(yīng)。T-helper (Th) 1 細(xì)胞、細(xì)胞毒性 CD8 + T 細(xì)胞和自然殺傷細(xì)胞是抗腫瘤免疫的主要效應(yīng)細(xì)胞，而調(diào)節(jié)性 T 細(xì)胞和髓源性抑制細(xì)胞等細(xì)胞與抗腫瘤負(fù)相關(guān)免疫。Th2 細(xì)胞和 Th17 細(xì)胞已被證明具有促腫瘤和抗腫瘤活性。各種免疫細(xì)胞的遷移特性對其功能至關(guān)重要，并受趨化因子超家族的嚴(yán)格調(diào)控。在這篇綜述中，我們總結(jié)了各種免疫細(xì)胞在腫瘤免疫中的作用以及趨化因子超家族對它們的遷移調(diào)節(jié)。我們還評估了靶向趨化因子和趨化因子受體在癌癥免疫治療中的治療可能性。

細(xì)胞搖瓶

Tumor immunity is initiated by the recognition of tumor antigens by the immune system [1]. Antigen priming and effector cell differentiation are regulated by complex processes involving various cell populations, cytokines, and chemokines [1,2,3]. While CD4+ helper T cells are known to orchestrate immune responses, CD4+ T cells are heterogenous and composed of various functional subsets including T-helper (Th) 1 cells, Th2 cells, Th17 cells, and regulatory T (Treg) cells [4,5]. These T cell subsets are characterized by the secretion of signature cytokines and differentially involved in tumor immunity [4,5]. Furthermore, CD8+ cytotoxic lymphocytes (CTLs) and natural killer (NK) cells play direct roles in the elimination of tumor cells. Tumor tissues are also highly enriched with innate immune cells such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs) [6,7]. These various immune cells are known to express characteristic chemokine receptors and are elaborately regulated in their migration and tissue localization by respective chemokine ligands [8,9,10]. Accordingly, some chemokines and their receptors may be involved in the elimination of tumor cells by recruiting anti-tumor effector cells, whereas others may promote tumor progression by attracting immunosuppressive cells. In addition, some chemokines and their receptors are known to play critical roles in the interactions of dendric cells (DCs) and T cells [11,12,13,14]. Thus, the chemokine superfamily has a multifaceted role in host tumor immunity. In this review, we overview the roles of various immune cells and the chemokine superfamily in host immune responses to tumor cells in order to assess the possibility of targeting chemokines and chemokine receptors for cancer immunotherapy.

腫瘤免疫是由免疫系統(tǒng)識別腫瘤抗原引發(fā)的[ 1 ]。抗原引發(fā)和效應(yīng)細(xì)胞分化受到涉及各種細(xì)胞群、細(xì)胞因子和趨化因子的復(fù)雜過程的調(diào)節(jié) [ 1 , 2 , 3 ]。雖然已知CD4 +輔助 T 細(xì)胞協(xié)調(diào)免疫反應(yīng)，但 CD4 + T 細(xì)胞是異質(zhì)的，由各種功能亞群組成，包括 T 輔助 (Th) 1 細(xì)胞、Th2 細(xì)胞、Th17 細(xì)胞和調(diào)節(jié)性 T (Treg) 細(xì)胞 [ 4 , 5 ]。這些 T 細(xì)胞亞群的特點(diǎn)是分泌特征性細(xì)胞因子，并與腫瘤免疫有差異 [ 4 ,5 ]。此外，CD8 +細(xì)胞毒性淋巴細(xì)胞 (CTL) 和自然殺傷 (NK) 細(xì)胞在消除腫瘤細(xì)胞中起直接作用。腫瘤組織還高度富含先天免疫細(xì)胞，例如髓源性抑制細(xì)胞 (MDSC)、腫瘤相關(guān)巨噬細(xì)胞 (TAM) 和腫瘤相關(guān)中性粒細(xì)胞 (TAN) [ 6 , 7 ]。已知這些不同的免疫細(xì)胞表達(dá)特征性趨化因子受體，并通過各自的趨化因子配體在它們的遷移和組織定位中精心調(diào)節(jié) [ 8 , 9 , 10]。因此，一些趨化因子及其受體可能通過招募抗腫瘤效應(yīng)細(xì)胞參與消除腫瘤細(xì)胞，而另一些可能通過吸引免疫抑制細(xì)胞來促進(jìn)腫瘤進(jìn)展。此外，已知一些趨化因子及其受體在樹突細(xì)胞 (DC) 和 T 細(xì)胞的相互作用中發(fā)揮關(guān)鍵作用 [ 11 , 12 , 13 , 14 ]。因此，趨化因子超家族在宿主腫瘤免疫中具有多方面的作用。在這篇綜述中，我們概述了各種免疫細(xì)胞和趨化因子超家族在宿主對腫瘤細(xì)胞的免疫反應(yīng)中的作用，以評估靶向趨化因子和趨化因子受體用于癌癥免疫治療的可能性。

細(xì)胞工廠

As described in this article, a diverse array of immune cells is now known to be involved in host tumor immunity and infiltrates into tumor tissues, generating a highly complex cell population in the tumor microenvironment [198]. Immune cells can have either anti-tumor or pro-tumor activities depending on their effector functions. These cells also express selective but often overlapping chemokine receptors and infiltrate into tumor tissues via chemokines produced by cells including tumor cells, infiltrating immune cells, and stromal cells [198]. To make matters more complex, tumor cells often express several chemokine receptors, and the corresponding chemokines are potentially involved in tumor cell functions such as proliferation, metastasis, and stemness [10,234]. Furthermore, it is known that some chemokines are positively and others negatively involved in angiogenesis [235]. Thus, targeting chemokines or chemokine receptors for cancer immunotherapy is an attractive but highly challenging task. However, after the recent success of immune checkpoint inhibitors in cancer immunotherapy, drugs targeting chemokines or chemokine receptors may have a new possibility as an adjunct drug for the main cancer immunotherapy. This is partly because the immune checkpoint inhibitors are beneficial in only a fraction of patients and one of the mechanisms of such primary resistance is considered to be the presence of potent immunosuppressive effector cells such as Treg cells and MDSCs in the tumor microenvironment. Thus, drugs targeting chemokines or chemokine receptors may provide a new tool to functionally suppress immunosuppressive cells. Indeed, some recent preclinical (Table 2) and clinical studies (Table 3) with drugs blocking chemokine receptors, such as CCR4, CCR8, CXCR2, and CXCR4, have shown some promising results and warrant further studies [196,214]. Collectively, it is hoped that drugs targeting the members of the chemokine superfamily may have a successful clinical application in cancer immunotherapy in near future.

PETG血清培養(yǎng)基瓶

如本文所述，現(xiàn)在已知多種免疫細(xì)胞參與宿主腫瘤免疫并浸潤到腫瘤組織中，在腫瘤微環(huán)境中產(chǎn)生高度復(fù)雜的細(xì)胞群 [ 198 ]。免疫細(xì)胞可以具有抗腫瘤或促腫瘤活性，這取決于它們的效應(yīng)功能。這些細(xì)胞還表達(dá)選擇性但通常重疊的趨化因子受體，并通過包括腫瘤細(xì)胞、浸潤性免疫細(xì)胞和基質(zhì)細(xì)胞在內(nèi)的細(xì)胞產(chǎn)生的趨化因子浸潤到腫瘤組織中 [ 198 ]。更復(fù)雜的是，腫瘤細(xì)胞通常表達(dá)幾種趨化因子受體，相應(yīng)的趨化因子可能參與腫瘤細(xì)胞的增殖、轉(zhuǎn)移和干性等功能[ 10, 234 ]。此外，眾所周知，一些趨化因子積極參與血管生成，而另一些則消極參與血管生成 [ 235]。因此，針對癌癥免疫治療的趨化因子或趨化因子受體是一項(xiàng)有吸引力但極具挑戰(zhàn)性的任務(wù)。然而，在近期免疫檢查點(diǎn)抑制劑在癌癥免疫治療中取得成功后，靶向趨化因子或趨化因子受體的藥物可能成為主要癌癥免疫治療的輔助藥物。這部分是因?yàn)槊庖邫z查點(diǎn)抑制劑僅對一小部分患者有益，而這種原發(fā)性耐藥的機(jī)制之一被認(rèn)為是腫瘤微環(huán)境中存在有效的免疫抑制效應(yīng)細(xì)胞，如 Treg 細(xì)胞和 MDSC。因此，靶向趨化因子或趨化因子受體的藥物可能提供一種新的工具來功能性地抑制免疫抑制細(xì)胞。事實(shí)上，最近的一些臨床前研究（表 2) 和使用阻斷趨化因子受體的藥物（如 CCR4、CCR8、CXCR2 和 CXCR4 ）進(jìn)行的臨床研究（表 3 ）已顯示出一些有希望的結(jié)果，值得進(jìn)一步研究 [ 196 , 214 ]?？偟膩碚f，希望針對趨化因子超家族成員的藥物在不久的將來可能在癌癥免疫治療中獲得成功的臨床應(yīng)用。

關(guān)鍵詞： 趨化因子,趨化因子受體,th1,th2, th17,監(jiān)管 T, 樹突狀細(xì)胞,巨噬細(xì)胞,中性粒細(xì)胞,腫瘤微環(huán)境,chemokine,chemokine receptor,Th1,Th2,Th17,regulatory T,dendritic cell,macrophage, neutrophil, tumor microenvironment

來源：MDPI https://www.mdpi.com/2072-6694/13/23/6132/htm