化療藥物靶向腫瘤相關免疫抑制性細胞的研究進展

·生物治療·

化療藥物靶向腫瘤相關免疫抑制性細胞的研究進展

蔣琦，錢其軍 (東方肝膽外科醫院腫瘤生物治療科、病毒基因治療實驗室，上海 200438)

[摘要]腫瘤相關免疫抑制性細胞在腫瘤的發生、發展過程中發揮重要的免疫抑制作用，腫瘤的發展和轉移常伴有這些細胞的異常聚集。調節性T細胞(regulatory T cells, Treg)和髓系來源的抑制性細胞(myeloid-derived suppressor cells，MDSC)是免疫抑制性細胞網絡的主要成分，它們通過直接或間接作用負向調節其他免疫細胞，抑制抗腫瘤的免疫反應。最新研究顯示，有些常規化療藥物除可直接殺傷腫瘤細胞外，還可降低Treg和MDSC的數量，抑制其功能，從而增強抗腫瘤免疫功能。因此，將化療藥物作為預處理方案，憑借其免疫調節作用聯合后續的過繼性細胞免疫治療可有效增強抗腫瘤免疫應答?；瘜W免疫治療策略將改變人們對傳統化療抗腫瘤地位的認識，繼而更加合理地應用化療藥物。

[關鍵詞]化療藥物；調節性T細胞；髓系來源的抑制性細胞；化學免疫治療；免疫抑制性細胞

[基金項目]國家科技重大專項資助項目(No.2013ZX10002-010-007)

[作者簡介]蔣琦，碩士研究生.研究方向：惡性腫瘤化療和免疫治療的臨床與基礎研究.E-mail: stjiangqichina@163.com

[通訊作者]錢其軍，教授, 博士生導師. 研究方向： 腫瘤基因-病毒治療和免疫治療、循環腫瘤細胞研究. E-mail: qianqj@sino-gene.cn

[中圖分類號]R456，R73[文獻標志碼]A

DOI[]10.3969/j.issn.1006-0111.2015.02.019

[收稿日期]2014-12-18[修回日期]2015-01-26

Chemotherapeutic targeting of cancer-induced immunosuppressive cells: an update research

JIANG Qi, QIAN Qijun (Laboratory of Gene and Viral Therapy, Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China)

Abstract[]Cancer-induced immunosuppressive cells play an important immunosuppressive role during the tumor development process, and the development and progression of tumors are always accompanied with abnormal accumulation of cancer-induced immunosuppressive cells. Regulatory T lymphocytes (Treg) and myeloid-derived suppressor cells (MDSC) are major components of these inhibitory cellular networks, and they can inhibit antitumor immune response through multiple mechanisms. Recent studies have provided evidence that beyond their direct cytotoxic or cytostatic effects on cancer cells, some conventional chemotherapeutic drugs and agents used in targeted therapies can promote the elimination or inactivation of suppressive Tregs or MDSCs, resulting in enhanced anti-tumor immunity. Hence, chemotherapeutics, used as a preconditioning regimen and combined with subsequent immunotherapy, can promote anti-tumor immune response. Anticancer chemoimmunotherapy strategy will change the recognization of the role for conventional chemotherapy in anticancer treatment, and it will be helpful to optimize the chemotherapy strategies more reasonably.

[Key words]chemotherapeutics; regulatory T cell; myeloid-derived suppressor cell; chemoimmunotherapy; cancer-induced immunosuppressive cell

一直以來，腫瘤生物學領域的探索幾乎完全集中于腫瘤細胞本身的研究，而對腫瘤細胞以外的腫瘤基質組成的腫瘤微環境很少關注。近年的臨床和實驗研究業已證實，腫瘤的形成是癌細胞及基質中多種細胞相互作用的共同結果。腫瘤基質由免疫細胞、成纖維細胞、血管內皮等細胞成分以及細胞外基質構成[1]。其中，腫瘤相關免疫抑制性細胞，主要有調節性T細胞(regulatory T cells, Treg)、髓系來源的抑制性細胞(myeloid-derived suppressor cells，MDSC)、腫瘤相關巨噬細胞(tumor-associated macrophage, TAM)和不成熟的樹突狀細胞(immature dendritic cells,iDC)，對腫瘤的免疫逃逸和免疫療法的低效性起關鍵作用[2-4]。隨著基礎研究和臨床試驗的深入，化療藥物不再是一種純粹的細胞毒性藥物，其免疫調節作用逐漸受到重視。本文就近年來最重要的2種免疫抑制性細胞(Treg和MDSC)的免疫抑制機制及其化學免疫治療策略作一綜述。

1Treg和化療藥物

1.1Treg20世紀70年代就提出抑制性T細胞這一概念[5]，直到 1995年，研究才明確CD25(IL-2受體α鏈)可作為小鼠Treg的重要表型標記[6]，此后Treg在腫瘤免疫逃逸中的作用備受關注。在人體內，Treg是一個異質性群體，主要包括CD4+CD125highTreg、Tr1(IL-10+T細胞)和TH3(TGF-β+T細胞)，Foxp3是Treg的一個特異性的轉錄因子。其中，CD4+CD125highFoxp3+Treg在多種人體腫瘤，包括肺癌、乳腺癌、胃癌、肝癌、腎癌、卵巢癌等實體腫瘤以及淋巴瘤等血液腫瘤中都存在，在某些腫瘤中的數量還與其預后密切相關，是一個獨立的預后因子。Treg發揮免疫抑制作用的機制主要有：①通過免疫抑制因子，如白細胞介素10(IL-10)、轉化生長因子β(TGF-β)等抑制效應細胞的功能；②通過顆粒酶和穿孔素直接殺傷效應細胞；③影響效應細胞的代謝，如高表達CD25大量消耗IL-2、產生腺苷抑制效應細胞增殖；④影響樹突狀細胞(DC)的功能進而影響T細胞的活化、誘導及增殖[7]。

1.2靶向Treg的化療藥物環磷酰胺(cyclophosphamide，CTX)，是一種烷化劑，可與DNA交聯，抑制DNA合成，用于治療乳腺癌、卵巢癌、多發性骨髓瘤和淋巴瘤，是第一個被報道能夠抑制Treg逆轉免疫耐受的藥物[8]。多項研究表明，CTX能清除荷瘤動物體內的Treg，由于大劑量CTX同時還可去除其他免疫細胞，凈效應為抑制抗腫瘤免疫反應。而小劑量CTX對其他免疫細胞的影響小，因此能增強機體的抗腫瘤免疫反應[9,10]。另一項研究顯示，小劑量CTX能引起小鼠體內和體外Treg的凋亡而不影響CD4+CD25-T細胞的活力；CTX是通過下調FoxP3和GITR蛋白來抑制Treg的功能[11]。許多臨床試驗也表明，小劑量CTX能減輕CD4+CD25+Treg的影響，增強TH1細胞，從而扭轉腫瘤誘導的免疫偏倚，促發腫瘤免疫。疫苗免疫之前應用小劑量CTX有利于潛在的高活性CD8+T細胞的募集[12]。最近一項臨床試驗證實，疫苗免疫前1 d給予CTX(200～300 mg/m2)和接種前7 d應用CTX(600 mg/m2)都能清除人體內的Treg[13]。此外，CTX節拍式給藥可以清除晚期腫瘤患者體內CD4+CD25+T細胞并恢復T細胞和自然殺傷(NK)細胞的有效作用[14]。因此，從化學免疫治療的角度來看，CTX的用藥劑量、給藥方式和順序都對Treg有影響，需進一步優化和更多的臨床試驗驗證。

紫杉醇(paclitaxel，PTX)，屬于紫杉烷類，可與微管蛋白的β亞單位結合，影響微管的聚合，抑制有絲分裂，最終導致細胞死亡。有研究報道，標準劑量PTX應用于晚期非小細胞肺癌患者，可選擇性地減少Treg數量和抑制Treg功能，同時保留效應T細胞的功能。PTX的選擇性作用歸結于其上調Treg的死亡受體Fas，而對效應T細胞不起作用[15]。在小鼠肺癌模型中，PTX可能通過影響凋亡調節蛋白Bcl-2/Bax的表達而誘導Treg凋亡[16]。多西他賽(docetaxel，DTX)同樣具有免疫刺激特性，Garnett等[17]證實DTX可降低Treg數量，但對Treg的功能無影響；增強CD8+T細胞對CD3交聯的應答，對CD4+T細胞無作用；增強疫苗的抗原特異性T細胞應答，降低了小鼠的腫瘤負荷。

標準劑量氟達拉濱(fludarabine，FA)對Treg具有抑制作用。Beyer等[18]發現慢性淋巴細胞白血病患者接受FA治療后，體內Treg數量顯著減少；體外實驗發現與FA共培養的Treg有70% 表達凋亡標志，較CD4+CD25-T細胞敏感；體外混合淋巴細胞反應顯示，經FA化療后患者的Treg對CD4+CD25-T細胞的抑制作用減弱。

在大鼠神經膠質瘤模型中顯示小劑量替莫唑胺(temozolomide，TEM)節拍式給藥能減少Treg在總CD4+T細胞中的比例，并且降低Treg的活性[19]。在晚期黑色素瘤患者中TEM能減少Treg數量的現象被進一步證實[20]。還有研究表明，用吉西他濱(gemcitabine，GEM)和FOLFOX4治療轉移性結直腸癌，再行皮下注射集落刺激因子(GM-CSF)和IL-2，可以使65%的患者Treg明顯減少，該發現與70%的對治療的客觀反應率有關[21]。來那度胺、泊馬度胺通過減少FoxP3表達來抑制Treg的增殖和功能，但具體機制不明[22]。在A20淋巴瘤模型中，顯示來那度胺能同時降低Treg和MDSC的數量。

2MDSC和化療藥物

2.1MDSC在荷瘤小鼠的脾臟、血液及腫瘤組織廣泛存在著一群強免疫抑制功能的細胞群體，來源于骨髓祖細胞和未成熟髓細胞，是樹突狀細胞、巨噬細胞或粒細胞的前體，稱為髓系來源的抑制性細胞。小鼠腫瘤動物模型中，這群細胞共表達髓系分化抗原Gr1和CD11b，可分為2個亞型：粒細胞樣的MDSC(CD11b+Ly6G+Ly6Clow)和單核細胞樣的MDSC(CD11b+Ly6G-Ly6Chigh)[3]。人體腫瘤MDSC的最基本識別特征還沒有公認的標準，現有的研究越來越多地用CD33、CD11b、HLA-DR、Lin、CD14、CD15等作為MDSC的表面標志，或用以上分子的不同組合作為腫瘤患者MDSC的鑒定標志。在多種腫瘤中發現MDSC表型為CD33和(或)CD11b表達陽性，而HLA-DR和(或)Lin不表達或低表達。與小鼠MDSC相似，人MDSC也可分為單核系MDSC(monocytic-MDSC、M-MDSC)和粒系MDSC (granulocytic-MDSC、G-MDSC)，人體M-MDSC表達CD14，而G-MDSC表達CD15，這2類MDSC均表達CD11b和CD33，不表達或低表達HLA-DR和Lin。MDSC主要從兩方面促進腫瘤的發展：① MDSC能表達多種促血管生成因子，如血管內皮生長因子(VEGF)、堿性成纖維細胞生長因子(bFGF)和(MMP)，直接促進腫瘤血管形成。②MDSC能通過高表達的精氨酸酶1(ARG1)、誘導型一氧化氮合成酶(iNOS)和活性氧簇(ROS)抑制T細胞介導的適應性抗腫瘤免疫和NK細胞與巨噬細胞介導的天然抗腫瘤免疫。例如，表達ARG1來分解T細胞賴以活化的精氨酸，下調TCRδ鏈和抑制歸巢受體CD62L的表達；誘導Treg的產生；分泌IL-10抑制巨噬細胞和DC的功能，阻斷NKG2D或膜型TGF-β抑制NK細胞功能[23]。

2.2靶向MDSC的化療藥物吉西他濱(gemcitabine，GEM)是一種嘧啶核苷類似物的抗代謝藥，可以抑制核酸還原酶和DNA聚合酶α，阻止DNA的合成。臨床上廣泛用于胰腺癌、肺癌、乳腺癌等多種腫瘤的治療。在多種腫瘤動物模型中，GEM通過降低MDSC的數量來抵抗腫瘤免疫。同樣地，另一種抗代謝藥氟尿嘧啶(5-Fu)小劑量應用時也能誘導MDSC凋亡，而對T細胞、B細胞及NK細胞的數量沒有明顯影響，機制可能是MDSC低表達胸苷酸合成酶[24]。因此，GEM對MDSC的作用主要表現為誘導凋亡。

多西他賽(docetaxel，DTX)是PTX的類似物，主要通過抑制MDSC的STAT3磷酸化和促使MDSC向M1分化來減弱MDSC的抑制作用[25]。動物實驗發現，DTX能有效抑制小鼠腫瘤生長并降低MDSC在小鼠脾臟內的數量，使細胞毒性T淋巴細胞反應性提高。經全身照射治療的機體產生淋巴細胞缺乏癥后，MDSC和調節性T細胞可以很快恢復其數量和功能，而加用DTX治療則能有效阻止MDSC的恢復，提高放射治療的療效[26]。Kodumudi[26]等研究發現，DTX處理組小鼠腫瘤微環境中的MDSC與對照組相比明顯減少，進一步研究發現，處理組有高達40% 的MDSC表達CCR7表型，而CCR7正是M1型巨噬細胞的表型。體外實驗顯示，DTX作用24 h后，MDSC上巨噬細胞的分化標志MHC-Ⅱ、CD11c、CD86表達均上調。同時，DTX可以誘導M2型巨噬細胞凋亡卻對M1型細胞有保護作用。由此可見，DTX對MDSC的作用表現為多方面，其中一個重要方面即表現為促進MDSC的分化成熟。另外，作為紫杉烷類的PTX，在體外1 nmol/L的PTX不能誘導MDSC的凋亡但卻可以促使MDSC分化為DC，揭示了低劑量PTX在動物實驗中降低MDSC水平的過程[27]。

阿霉素(adriamycin，ADM)是蒽環類抗生素，其代謝活性物嵌入DNA堿基中形成復合體，抑制DNA合成和轉錄。在多種荷瘤小鼠模型中發現ADM具有免疫調節效應，能選擇性地清除和滅活MDSC，機制可能包括：① ADM優先靶向高增殖活性細胞，在非干預狀態下的荷瘤小鼠體內MDSC的增殖活力遠高于T細胞和NK細胞；② ADM能提高已較其他免疫細胞高表達ROS的MDSC持續高表達ROS，導致ROS依賴的細胞凋亡。盡管ADM的選擇性作用是暫時的，但優先靶向MDSC的作用提高了效應T細胞與免疫抑制性細胞的比例，為CD4+T細胞、CD8+T細胞和NK細胞發揮抗腫瘤免疫提供了最基本的條件。值得重視的是，與單用ADM比較，小鼠在接受含ADM的聯合治療后，其體內MDSC數量能較長時間維持低水平[28]。這種現象進一步提示了化學免疫治療策略中免疫刺激后進一步聯合治療的可能性和重要性。

阿扎胞苷(5-azacytidine，AZA)是一種去甲基化藥物，在小鼠TC-1/A9和TRAMP-C2腫瘤模型中可觀察到，能減少MDSC聚集和抑制MDSC功能[29]。但是化療藥物并非都能減輕MDSC的負荷，某些藥物反而可以誘導MDSC生成。CTX在非荷瘤小鼠中可以誘導MDSC短暫升高。研究顯示，CTX和腫瘤均可誘導正常小鼠MDSC增多，兩者誘導的MDSC都會加速腫瘤的生長，但是它們的亞型和抑制免疫功能的機制不同。CTX誘導的MDSC中單核細胞樣MDSC的比例較高，抑制性基因水平表達較低，經干擾素-γ刺激之后，其表達上調，但抑制功能仍不及腫瘤誘導的MDSC。而荷瘤小鼠給予CTX治療后誘導的MDSC表型和功能介于上述兩者之間，且具有更強的可塑性[30]。

3結語

基于對宿主-腫瘤相互作用的免疫細胞和分子機制，以及腫瘤化療藥對該機制作用的深入認識，傳統化療藥物靶向作用于腫瘤誘導產生的免疫抑制細胞網絡，將是一個新的研究熱點。策略性的聯合化療藥的免疫治療來改變宿主的整體內環境和局部腫瘤微環境，以及改變免疫耐受和免疫抑制的不同機制，可以維持有效、持久的抗腫瘤免疫應答。但需注意的是，在實際應用時，化療藥物的可能的分子機制、藥物劑量和用藥時機等細節問題仍然需要進一步設計和優化。尚需開展更多的相關研究，特別是大樣本臨床試驗，使化學免疫治療廣泛用于惡性腫瘤的治療成為現實。

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[19]Banissi C, Ghiringhelli F, Chen L,etal. Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model[J]. Cancer Immunol Immunother,2009,58(10):1627-1634.

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[23]Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer[J]. J Immunol,2009,182(8):4499-4506.

[24]Vincent J, Mignot G, Chalmin F,etal. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity[J]. Cancer Res,2010,70(8):3052-3061.

[25]Kodumudi KN, Woan K, Gilvary DL,etal. A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers[J]. Clin Cancer Res,2010,16(18):4583-4594.

[26]Kodumudi KN, Weber A, Sarnaik AA,etal. Blockade of myeloid-derived suppressor cells after induction of lymphopenia improves adoptive T cell therapy in a murine model of melanoma[J]. J Immunol,2012,189(11):5147-5154.

[27]Michels T, Shurin GV, Naiditch H,etal. Paclitaxel promotes differentiation of myeloid-derived suppressor cells into dendritic cellsinvitroin a TLR4-independent manner[J]. J Immunotoxicol,2012,9(3):292-300.

[28]Alizadeh D, Trad M, Hanke NT,etal. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer[J]. Cancer Res,2014,74(1):104-118.

[29]Mikysková R, Indrová M, Vlková V,etal. DNA demethylating agent 5-azacytidine inhibits myeloid-derived suppressor cells induced by tumor growth and cyclophosphamide treatment[J]. J Leukoc Biol,2014,95(5):743-753.

[30]Mikysková R, Indrová M, Pollaková V,etal. Cyclophosphamide-induced myeloid-derived suppressor cell population is immunosuppressive but not identical to myeloid-derived suppressor cells induced by growing TC-1 tumors[J]. J Immunother,2012,35(5):374-384. KN, Weber A, Sarnaik AA,etal. Blockade of myeloid-derived suppressor cells after induction of lymphopenia improves adoptive T cell therapy in a murine model of melanoma[J]. J Immunol,2012,189(11):5147-5154.

[27]Michels T, Shurin GV, Naiditch H,etal. Paclitaxel promotes differentiation of myeloid-derived suppressor cells into dendritic cellsinvitroin a TLR4-independent manner[J]. J Immunotoxicol,2012,9(3):292-300.

[28]Alizadeh D, Trad M, Hanke NT,etal. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer[J]. Cancer Res,2014,74(1):104-118.

[29]Mikysková R, Indrová M, Vlková V,etal. DNA demethylating agent 5-azacytidine inhibits myeloid-derived suppressor cells induced by tumor growth and cyclophosphamide treatment[J]. J Leukoc Biol,2014,95(5):743-753.

[30]Mikysková R, Indrová M, Pollaková V,etal. Cyclophosphamide-induced myeloid-derived suppressor cell population is immunosuppressive but not identical to myeloid-derived suppressor cells induced by growing TC-1 tumors[J]. J Immunother,2012,35(5):374-384.

[本文編輯]李睿旻