腦轉(zhuǎn)移（BrM）的診斷長期以來一直被視為毫無希望的死亡判決，幾乎沒有治療選擇可以緩解癥狀或延長生命。在少數(shù)可用的治療選擇中，腦部放療（RT）和手術(shù)切除一直是治療的基石。在過去幾年中，免疫治療（IT）作為一種重要力量，單獨(dú)或與傳統(tǒng)治療聯(lián)合應(yīng)用，已經(jīng)成為對(duì)抗腦轉(zhuǎn)移瘤擴(kuò)散和減小腫瘤負(fù)擔(dān)的重要手段。本綜述匯編了近期的研究報(bào)告，描述了IT在不同癌癥腦轉(zhuǎn)移瘤治療中的潛在作用。本文還探討了腦轉(zhuǎn)移瘤腫瘤微環(huán)境對(duì)癌癥擴(kuò)散的調(diào)控作用，以及IT在減輕擴(kuò)散中的作用。最后，本文還關(guān)注IT在腦轉(zhuǎn)移瘤治療中的未來發(fā)展和新的臨床試驗(yàn)介紹。

最新的有關(guān)腦轉(zhuǎn)移治療的文獻(xiàn)解讀

圖1. 腦轉(zhuǎn)移的機(jī)制和免疫治療進(jìn)展時(shí)間表

1. ?循環(huán)腫瘤細(xì)胞或轉(zhuǎn)移細(xì)胞使原發(fā)性黑色素瘤、肺癌、乳腺癌、腎癌和結(jié)直腸癌通過血管侵犯進(jìn)入血液或系統(tǒng)循環(huán)，到達(dá)大腦，并通過血腦屏障。在大腦中，這些轉(zhuǎn)移細(xì)胞通過L1CAM介導(dǎo)的血管選擇性逃避凋亡，各種其他因素如STAT3、PI3K、S6GALNAC5和組織蛋白酶S幫助這些細(xì)胞定植和生長。這些細(xì)胞還將其代謝調(diào)節(jié)為高OXPHOS，并變得較少糖酵解。

2. 與各種免疫療法在治療腦轉(zhuǎn)移瘤中的意義相關(guān)的時(shí)間軸進(jìn)展。

圖2.?腦轉(zhuǎn)移與腫瘤免疫治療

1. ?除了轉(zhuǎn)移的腫瘤細(xì)胞外，腦轉(zhuǎn)移瘤的腫瘤微環(huán)境(TME)包括獨(dú)特的細(xì)胞類型，包括星形膠質(zhì)細(xì)胞/活化星形膠質(zhì)細(xì)胞、小膠質(zhì)細(xì)胞、髓系抑制細(xì)胞(MDSCs)和神經(jīng)元。星形膠質(zhì)細(xì)胞/小膠質(zhì)細(xì)胞釋放的神經(jīng)分泌物支持了腦轉(zhuǎn)移的癌細(xì)胞在腦微環(huán)境中的生長。腦轉(zhuǎn)移癌細(xì)胞有多種機(jī)制可以逃避免疫細(xì)胞的攻擊，可能通過在癌細(xì)胞/免疫細(xì)胞中上調(diào)PD-L1/PD-1軸、過表達(dá)CD44等細(xì)胞表面受體，或通過分泌外泌體或其他代謝產(chǎn)物增強(qiáng)免疫抑制性調(diào)節(jié)T細(xì)胞（Treg）的招募。

2. ?目前正在評(píng)估用于腦轉(zhuǎn)移瘤治療的各種免疫治療，包括抗PD-L1/抗PD-1和抗CTLA4。免疫治療增強(qiáng)T效應(yīng)細(xì)胞（CD8+）的活性，或誘導(dǎo)腫瘤抗原呈遞，從而引起免疫激活，促進(jìn)癌細(xì)胞死亡。

表1. 免疫療法治療腦轉(zhuǎn)移和軟腦膜轉(zhuǎn)移

表2. 治療腦轉(zhuǎn)移瘤中使用的各種癌癥類型的關(guān)鍵免疫治療藥物

圖3.目前臨床上的不同免疫療法及其在治療腦轉(zhuǎn)移中的應(yīng)用

腦轉(zhuǎn)移發(fā)生在癌癥細(xì)胞從其原發(fā)腫瘤部位（通常是從乳腺、肺、腎/腎、結(jié)腸和黑色素瘤）遷移到大腦。圖中顯示的免疫療法是在臨床上結(jié)合放療（RT）/立體定向放射外科（SRS）治療腦轉(zhuǎn)移。除了目前的ITs外，抗體-藥物偶聯(lián)物（ADC）和CART細(xì)胞的應(yīng)用也可以用來提高這些治療模式治療BrM的療效。

圖4. 腫瘤微環(huán)境的代謝環(huán)境及其對(duì)免疫治療或T細(xì)胞功能的影響

1. ?Metabolic struggle and/ or metabolic reprogramming transpire between various tumor-infiltrating immune cells and tumor cells. Both T cells and tumor cells preferentially utilize glucose to meet their energy demands. Due to high proliferation potential and high energy needs, tumor cells metabolize most of the glucose through aerobic glycolysis and produce high levels of lactic acid (lactate) in the TME, thereby, decreasing glucose availability for immune cells. The lactate-enriched and glucose-deprived TME impairs T cell functioning, recruits more (regulatory T cells) Tregs, and polarizes microglial cells towards a protumorigenic phenotype and tumor-associated macrophages (TAMs). There is further competition for amino acids, including glutamine/glutamate and tryptophan between T cells, myeloid-derived suppressor cells (MDSCs), and tumor cells. The availability of these amino acids in the TME that modulate T cell-mediated immune response, such as kynurenine (a product of tryptophan catabolism) produced by indoleamine 2,3-dioxygenase 1 (IDO1) present in tumor cells, MDSCs, and TAMs blocks activation of T cells and promotes the recruitment and production of immunosuppressive Treg cells. The brain microenvironment has high glutamine and tryptophan; therefore, tumor cells easily adapt to the brain microenvironment utilizes these amino acids for their growth and development. Lactate production in the TME also increases the expression of PD-1 on T cells and PD-L1 on tumor cells and suppresses the activity of immune cells.

2. The immunotherapeutic response of ITs could be enhanced by targeting the various metabolic regulators of tumor cells and immune cells. The utilization of inhibitors that specifically target glucose transporters (GLUT1), lactate production, IDO1 activity, and glutamine utilization in tumor cells could be a potential therapeutic strategy to enhance the efficacies of ITs in brain metastasis

參考文獻(xiàn)

Ahmad et al. Molecular Cancer (2023) 22:111?