綜述 審校

復(fù)旦大學(xué)附屬腫瘤醫(yī)院放療科，復(fù)旦大學(xué)上海醫(yī)學(xué)院腫瘤學(xué)系，上海 200032

乳腺癌輔助放療對(duì)抗腫瘤免疫影響的研究進(jìn)展

王小方綜述郭小毛審校

復(fù)旦大學(xué)附屬腫瘤醫(yī)院放療科，復(fù)旦大學(xué)上海醫(yī)學(xué)院腫瘤學(xué)系，上海 200032

免疫是機(jī)體的基本防御屏障，與乳腺癌的發(fā)生、發(fā)展、治療及預(yù)后密切相關(guān)。輔助放療是乳腺癌綜合治療的重要組成部分。傳統(tǒng)觀點(diǎn)認(rèn)為放療可直接破壞機(jī)體免疫細(xì)胞，進(jìn)而抑制機(jī)體免疫的抗腫瘤效果。而近期研究表明，放療可刺激免疫系統(tǒng)產(chǎn)生一系列積極反應(yīng)，有利于腫瘤殺傷過程中抗原的加工、提呈、識(shí)別及腫瘤的最終殺傷。臨床方面，放療聯(lián)合多種免疫靶向治療相繼進(jìn)入臨床試驗(yàn)階段。本文將對(duì)乳腺癌放療對(duì)抗腫瘤免疫影響的研究發(fā)展及現(xiàn)狀進(jìn)行介紹。

乳腺癌；放療；免疫

1 乳腺癌與免疫

2011年，Schreiber等［1］發(fā)表在Science中的一篇文章提出，腫瘤的發(fā)生是腫瘤生長及侵襲能力由弱到強(qiáng)，而機(jī)體免疫功能由活躍到沉默的一種此消彼長的過程，腫瘤的發(fā)生、發(fā)展、治療、預(yù)后等均與機(jī)體免疫密切相關(guān)。乳腺癌作為一種實(shí)體腫瘤，其發(fā)展過程亦有此特點(diǎn)。同時(shí)，對(duì)乳腺癌患者的臨床病理分析顯示，腫瘤組織或淋巴結(jié)中一些抗腫瘤和促瘤因素的數(shù)量或比例改變，如濾泡狀B細(xì)胞、Treg細(xì)胞數(shù)量及CD4+/CD8、TH2/ TH1的比例等，與腫瘤的分級(jí)、分期和患者的總生存率相關(guān)［2］，進(jìn)一步表明了乳腺癌與免疫的相關(guān)性。

經(jīng)典的抗腫瘤免疫包括抗原的提呈、識(shí)別，效應(yīng)細(xì)胞的活化和發(fā)揮免疫效應(yīng)幾個(gè)環(huán)節(jié)。但同時(shí)腫瘤細(xì)胞也通過多種方式免疫逃逸，如下調(diào)腫瘤抗原、削弱抗腫瘤免疫等。而放療作為一種治療手段，除直接殺滅腫瘤細(xì)胞外，還能一定程度影響免疫系統(tǒng)，進(jìn)而影響抗腫瘤免疫進(jìn)程，本文將從細(xì)胞及分子水平上綜述放療對(duì)乳腺癌抗腫瘤免疫的影響。

2 放射治療對(duì)乳腺癌抗腫瘤免疫影響

2.1 放射對(duì)抗腫瘤免疫的促進(jìn)作用

放射治療運(yùn)用電離射線殺滅腫瘤，與此同

時(shí)，電離射線也影響著免疫微環(huán)境，在免疫細(xì)胞的招募、腫瘤細(xì)胞的識(shí)別以及殺滅等多環(huán)節(jié)增強(qiáng)機(jī)體的抗腫瘤免疫，下文就放射線對(duì)抗腫瘤免疫各階段的影響加以闡述。

放療對(duì)免疫細(xì)胞的影響：傳統(tǒng)觀念認(rèn)為放療是免疫抑制性的，因其造成了免疫細(xì)胞的降低而抑制了機(jī)體的免疫功能。但近期研究發(fā)現(xiàn)，正是因?yàn)榉暖熆梢鸬土馨脱Y，機(jī)體為恢復(fù)穩(wěn)態(tài)而發(fā)生免疫細(xì)胞增殖，此殺滅、再生現(xiàn)象對(duì)消除因長期荷瘤而產(chǎn)生的無能T細(xì)胞有利［3］。且新增殖的細(xì)胞同時(shí)具備記憶細(xì)胞和效應(yīng)細(xì)胞的特征，能引發(fā)更快速有效的抗瘤效應(yīng)［4-6］。另有實(shí)驗(yàn)表明，低劑量放療能降低Treg細(xì)胞的比例和數(shù)量，使免疫反應(yīng)更容易被激發(fā)，使得低劑量放療具有不同程度的免疫促進(jìn)作用［7］。

免疫細(xì)胞的招募：免疫細(xì)胞隨血液循環(huán)于全身，當(dāng)局部炎性反應(yīng)遞質(zhì)如細(xì)胞因子、淋巴細(xì)胞、黏附分子等增多時(shí)，淋巴細(xì)胞穿出血管在局部組織的浸潤增多。體外實(shí)驗(yàn)表明，內(nèi)皮細(xì)胞表面黏附分子如ICAM、E-選擇素在放射后表達(dá)上調(diào)［8］。Wu等［9］的體內(nèi)實(shí)驗(yàn)也證實(shí)了這一現(xiàn)象。同時(shí)，趨化因子CXCL16在放射后亦有增高，吸引表達(dá)CXCR6的CD8+T細(xì)胞［10］。此外，射線引起的DNA損傷可直接或間接地引起核轉(zhuǎn)錄因子-κB(nuclear factor Kappa B，NF-кB)活化，導(dǎo)致直接調(diào)控參與促炎免疫反應(yīng)的分子如腫瘤壞死因子(tumor necrosis factor，TNF)的表達(dá)［11］。此類炎性反應(yīng)遞質(zhì)的增多進(jìn)一步引起局部抗腫瘤免疫的增強(qiáng)。

免疫的誘發(fā)階段：放療可引起細(xì)胞生命相關(guān)物質(zhì)如染色體、DNA、蛋白質(zhì)的損傷和破壞，導(dǎo)致細(xì)胞死亡。死亡的細(xì)胞釋放的細(xì)胞碎片于機(jī)體免疫系統(tǒng)形成一種“危險(xiǎn)信號(hào)”，即損傷相關(guān)分子模式(damage associated molecular patterns，DAMP)，可被固有免疫細(xì)胞如巨噬細(xì)胞、樹突狀細(xì)胞等通過細(xì)胞表面模式識(shí)別受體(pattern recognization receptor，PRR)識(shí)別，啟動(dòng)機(jī)體固有及適應(yīng)性免疫［12］。近期研究顯示，放療可引起乳腺癌細(xì)胞釋放一種重要的DAMP—HMGB-1，該因子能與DC表面PRRTLR-4結(jié)合啟動(dòng)免疫反應(yīng)［13］。放療作用于鈣網(wǎng)蛋白和ATP，產(chǎn)生類似的作用。鈣網(wǎng)蛋白被稱為“eat me”信號(hào)，放療后迅速向細(xì)胞表面移動(dòng)［14］；ATP在放療后也從細(xì)胞內(nèi)快速釋放［15］，二者均可與DC表面PRR結(jié)合引發(fā)后續(xù)免疫反應(yīng)。

抗原提呈和識(shí)別階段：MHC-I分子表達(dá)缺失、抗原提呈缺陷是常見的腫瘤免疫逃逸機(jī)制。體外實(shí)驗(yàn)表明，放射能引起乳腺癌細(xì)胞MHC-I表達(dá)增高［16］及抗原肽加工增強(qiáng)［17］，在一定程度上修復(fù)了這種免疫逃逸。適應(yīng)性免疫細(xì)胞的激活具有雙信號(hào)的特點(diǎn)，放療使B細(xì)胞、DC細(xì)胞表面共刺激分子CD80的表達(dá)增強(qiáng)［18］，致T細(xì)胞活化第二信號(hào)CD28-CD80增強(qiáng)，由此增強(qiáng)T細(xì)胞識(shí)別及活化過程的能力。

腫瘤殺滅階段：抗腫瘤免疫中腫瘤細(xì)胞的殺傷多依賴于CD8+T細(xì)胞和NK細(xì)胞。腫瘤細(xì)胞受到照射后表面Fas表達(dá)增高［19］，F(xiàn)as作為一種凋亡受體與CD8+T細(xì)胞和NK細(xì)胞表面Fas-L或TNF-a、TRAIL結(jié)合，啟動(dòng)凋亡程序，誘導(dǎo)凋亡。放射還可引起NK細(xì)胞激活型受體NKG2D表達(dá)增多，促進(jìn)NK/T細(xì)胞的活化［20］。此外，放射后死亡的細(xì)胞可釋放熱休克蛋白70，可將缺陷蛋白提呈于細(xì)胞表面由NK細(xì)胞識(shí)別并殺傷［21］。

2.2 放射對(duì)抗腫瘤免疫的抑制作用

大多數(shù)的腫瘤治療方式都有不同程度的免疫抑制作用。

對(duì)免疫細(xì)胞的影響：在放射治療過程中，機(jī)體免疫系統(tǒng)不可避免地接受到一定程度的輻射，造成免疫細(xì)胞的損傷破壞；另外，骨髓組織對(duì)射線具有較高的敏感性，放射治療可抑制骨髓起源細(xì)胞的產(chǎn)生，其中包括了原始免疫細(xì)胞［22］。

放療后絕大多數(shù)固有免疫細(xì)胞、適應(yīng)性免疫細(xì)胞計(jì)數(shù)即刻下降。放療后NK細(xì)胞表現(xiàn)出低活力，持續(xù)數(shù)周逐漸恢復(fù)［23］。其他一些固有免疫細(xì)胞如單核細(xì)胞、巨噬細(xì)胞等計(jì)數(shù)均有不

同程度的下降，多在6個(gè)月之內(nèi)得以恢復(fù)［24］。放療后，乳腺癌患者CD8+T、CD4+T細(xì)胞增殖及信號(hào)轉(zhuǎn)導(dǎo)受到抑制［25］，B細(xì)胞分泌功能降低，部分免疫球蛋白在1年之后仍低于治療前水平［26］。有報(bào)道顯示，一些患者淋巴細(xì)胞的恢復(fù)長達(dá)10年［27］。Treg則顯示出一定的放射抵抗性，局部放療后百分比增加［28］。

生物活性因子的改變：Sekar等［29］研究發(fā)現(xiàn)，放化療后凋亡的乳腺癌細(xì)胞能誘導(dǎo)DC分泌IL-27，誘導(dǎo)CD39+CD69+Treg生成，抑制了CTL的細(xì)胞毒性。同時(shí)，放療后侵襲相關(guān)性的趨化因子如SDF-1［2］、CXCL8［30］表達(dá)增多；抑制性細(xì)胞因子如TGF-分泌增加，多數(shù)抗腫瘤細(xì)胞因子如IFN-r，IL-2，IL-4分泌減少［23］。此外，放療后在環(huán)氧酶催化下前列腺素合成增多［31］，其中A2、D2、E2可抑制淋巴細(xì)胞對(duì)抗原的反應(yīng)，D2、E2抑制NK活力［32］，由此可部分解釋放療后免疫細(xì)胞的減少。

3 影響乳腺癌抗腫瘤免疫的多種放射相關(guān)因素

3.1 放射野對(duì)免疫的影響

Standish等［23］在臨床研究時(shí)發(fā)現(xiàn)，放射野增大時(shí)，免疫細(xì)胞的改變更為突出，可能與暴露于放射區(qū)域的淋巴管增多有關(guān)。

3.2 分割方式及劑量的影響

Lee等［33］發(fā)現(xiàn)與常規(guī)放療相比，單次大劑量放療增加了病灶中T細(xì)胞的浸潤。這可能與在一定范圍內(nèi)，隨放射劑量增大，多種抗腫瘤免疫相關(guān)因子，如MHC-I［17］、CXCL16［10］等表達(dá)增多有關(guān)。Dewan等［34］利用乳腺癌模型進(jìn)行相同的研究發(fā)現(xiàn)不同的放射方式有相似的局部腫瘤控制率，其中分割治療顯著增加了“旁觀者效應(yīng)”，更有利于遠(yuǎn)處腫瘤的控制，但治療方式對(duì)免疫的影響有待進(jìn)一步證實(shí)。

3.3 化放療序貫治療對(duì)免疫的影響

化放療序貫治療是乳腺癌最常采用的輔助治療方式，但在一定程度上會(huì)出現(xiàn)免疫毒性的疊加?？傮w來說，序貫治療對(duì)免疫系統(tǒng)的抑制強(qiáng)于單純放療［25］，但二者又各有側(cè)重。Kang等［35］對(duì)早期乳腺癌(Ⅰ～Ⅲ期)患者進(jìn)行研究，發(fā)現(xiàn)了序貫治療組更趨向于出現(xiàn)Th1型細(xì)胞因子抑制，而單純放療組則為Th2型。兩組免疫恢復(fù)情況也不盡相同，前組顯著延遲了細(xì)胞因子IL-2和CD4+T細(xì)胞亞群的恢復(fù)，且對(duì)NK細(xì)胞產(chǎn)生了短暫而明顯的抑制；而后組對(duì)IL-4的恢復(fù)延遲比較明顯。此外，在對(duì)不同乳腺癌分期與輔助治療后免疫抑制分析時(shí)，Ⅰ～Ⅱ期與Ⅲ期未發(fā)現(xiàn)有明顯差異。

4 放療在乳腺癌抗腫瘤免疫中的臨床應(yīng)用進(jìn)展

放療影響著機(jī)體抗腫瘤免疫的進(jìn)程，其或多或少的出現(xiàn)了免疫系統(tǒng)的抑制或損傷，為達(dá)到放療后最大抗腫瘤效應(yīng)，我們采用放療與免疫治療相結(jié)合修復(fù)這些損傷。

Treg是一種免疫抑制細(xì)胞，對(duì)放療相對(duì)抵抗。該細(xì)胞活化后持續(xù)表達(dá)CTLA-4，與B7配接后傳遞抑制信號(hào)。抗CTLA-4單抗可阻斷Treg細(xì)胞的抑制作用。乳腺癌動(dòng)物模型中放療+CTLA-4是一個(gè)成功的例子，聯(lián)合治療不僅能顯著增加腫瘤的局部控制率，優(yōu)化分割劑量后聯(lián)合治療還能最大限度地達(dá)到“旁觀者效應(yīng)”［34］，對(duì)遠(yuǎn)處腫瘤控制具有積極意義。放療聯(lián)合其他免疫治療方式，如體外激活DC細(xì)胞回輸荷瘤者體內(nèi)［36］、應(yīng)用諸如CpG寡脫氧核苷酸的TLR激動(dòng)劑［37］、TGF-抑制劑［38］、抗CD137、抗CD40、OX40、抗PD-1［39］等生物制劑在體外或動(dòng)物模型中取得了良好的抗腫瘤效果。多種放療聯(lián)合免疫治療相繼進(jìn)入臨床試驗(yàn)階段，Gulley等［40］對(duì)早期前列腺癌患者進(jìn)行Ⅱ期臨床試驗(yàn)，分為放療+PSA疫苗聯(lián)合組(17例)與單純放療組(9例)，聯(lián)合組輔以粒細(xì)胞集落刺激因子(GM-CSF)及低劑量白介素-2(IL-2)。試驗(yàn)表明，聯(lián)合組76%患者出現(xiàn)3倍以上的PSA特異性免疫應(yīng)答，并出現(xiàn)新的前列腺相關(guān)抗原免疫應(yīng)答，而單純放療組未出現(xiàn)相似改變。在聯(lián)合治療組20個(gè)月、單純放療組25.1個(gè)月的中位隨訪時(shí)間中，分別有2例發(fā)生復(fù)發(fā)。此次臨床試驗(yàn)證實(shí)了免疫制劑與放療聯(lián)合應(yīng)用的可行性，但仍需大樣本的隨機(jī)試驗(yàn)證實(shí)機(jī)體免疫學(xué)改變能否轉(zhuǎn)化為患者的生存獲益。此外，放療+自體DC細(xì)胞瘤內(nèi)注射［41-42］、放療+抗CTLA-4抗體(Ipilimuma)［43］等Ⅰ/Ⅱ期臨床試驗(yàn)都取得了令人

滿意的結(jié)果。但免疫系統(tǒng)復(fù)雜而精細(xì)，在人體中治療價(jià)值有待進(jìn)一步探索。

5 放療在抗腫瘤免疫中的前景

機(jī)體免疫與腫瘤發(fā)生、發(fā)展、治療、預(yù)后密不可分，放射治療影響著機(jī)體抗腫瘤免疫的進(jìn)程，目前研究主要集中于聯(lián)合免疫制劑增強(qiáng)放射后抗腫瘤免疫效果，并且在動(dòng)物實(shí)驗(yàn)中取得一定效果。但免疫系統(tǒng)復(fù)雜而精細(xì)，如何尋找到放療抑制免疫的上游調(diào)控點(diǎn)，消除放療對(duì)抗腫瘤免疫的不利影響，還有待我們進(jìn)一步探索。

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Progression of adjuvant radiotherapy upon breast cancer immunity

WANG Xiao-fang, GUO Xiaomao (Department of Radiation Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China)

Immunity is the basic defense barrier for body, and also closely related to the development, progression, treatment and prognosis of breast cancer. Adjuvant radiotherapy plays an important role in the multidisciplinary treatment of breast cancer. It has long been believed that radiotherapy was immunosuppressive because it could destroy the body’s immune cells directly. While recent studies have shown that radiotherapy can stimulate the host immune system in the antitumor process, including antigen processing, presentation, recognition, and eventually tumor-cell killing. In the clinical aspect, a variety of immune targeted therapies, combined with radiotherapy, have entered clinical trials. The article reviewed research progress and status of the in fl uence of breast cancer adjuvant radiotherapy on antitumor immunity.

Breast cancer; Radiotherapy; Immunity

10.3969/j.issn.1007-3969.2014.05.012

R737.9

A

1007-3639(2014)05-0392-05

2013-10-30

2014-02-19）

國家自然科學(xué)基金(No：81372430)。

郭小毛 E-mail:guoxm1800@126.com