【摘要】： 樹突狀細(xì)胞(Dendritic cell，DC)是目前發(fā)現(xiàn)的機(jī)體內(nèi)功能最強(qiáng)大的抗原呈遞細(xì)胞(Antigen-presenting cells，APC)，其表面的MHC類分子和MHC—肽復(fù)合物含量是其它APC的10～100倍。DC可有效地誘導(dǎo)初始T細(xì)胞(Naive T cell)增殖和應(yīng)答，促進(jìn)細(xì)胞毒性T淋巴細(xì)胞(Cytotoxic T lymphocytes，CTL)和輔助性T細(xì)胞(T help cells，Th)的生成，可見DC是機(jī)體免疫反應(yīng)的啟動者和參與者。由DC激活的T細(xì)胞介導(dǎo)的抗腫瘤免疫反應(yīng)是機(jī)體抗腫瘤免疫的主導(dǎo)力量。有報道稱，許多腫瘤組織中浸潤有樹突狀樣或表達(dá)DC表面標(biāo)志的細(xì)胞，但盡管腫瘤組織內(nèi)存在這類細(xì)胞，腫瘤細(xì)胞還是會逃脫免疫系統(tǒng)的監(jiān)視而過度生長，甚至發(fā)生浸潤和轉(zhuǎn)移。因此，有關(guān)腫瘤免疫逃逸機(jī)制的研究是當(dāng)前生物醫(yī)學(xué)的一個前沿?zé)狳c課題。目前，對于腫瘤細(xì)胞逃避DC對其表面抗原的提呈而發(fā)生免疫逃逸的機(jī)制尚未完全清楚。諸多研究指出，其機(jī)制可能是腫瘤細(xì)胞釋放多種抑制性的細(xì)胞因子如VEGF、TGF-β、IL-10、M-CSF、PGE2等使DC成熟和分化發(fā)生障礙，抑制了DC抗原提呈能力并減弱其激活T細(xì)胞的能力，使這些DC對活化信號表現(xiàn)出低反應(yīng)性。隨著DC研究的不斷深入，各種DC亞群包括具有負(fù)向免疫調(diào)控作用的調(diào)節(jié)性DC的發(fā)現(xiàn)，腫瘤浸潤DC的功能也變得更為復(fù)雜。腫瘤浸潤DC中是否也存在著具有抑制功能的DC亞群昵?是否該群DC不但不具備免疫監(jiān)視和免疫防御功能，反而會促進(jìn)腫瘤細(xì)胞的生長和轉(zhuǎn)移呢?基于這樣的考慮，我們利用新鮮分離的腫瘤細(xì)胞模擬腫瘤微環(huán)境與體外培養(yǎng)的DC共孵育，研究了腫瘤微環(huán)境對DC的表型和功能特征的影響，以期進(jìn)一步了解腫瘤微環(huán)境對DC的影響以及腫瘤浸潤DC對腫瘤生長和轉(zhuǎn)移的作用，為腫瘤免疫逃逸的機(jī)制研究增加新的認(rèn)識。 首先，我們選用小鼠肺癌細(xì)胞株3LL皮下接種C57BL／6小鼠，復(fù)制荷瘤小鼠模型，分離合適大小的腫瘤組織，用膠原酶消化后碾磨成單細(xì)胞懸液，讓其貼壁生長。一周后即可得到形態(tài)相似的，能夠生長的原代腫瘤細(xì)胞。新鮮分離的腫瘤細(xì)胞比腫瘤細(xì)胞系具有更好的性狀，更能模擬體內(nèi)的腫瘤微環(huán)境。我們制備了GM-CSF和IL-4培養(yǎng)了5天的小鼠骨髓來源的CD11c~+DC，此時CD11c~+DC細(xì)胞表面Ia、CD40、CD80、CD86的水平都比較低，具有較強(qiáng)的吞噬功能，可以認(rèn)為是一種不成熟DC。我們用新鮮分離的原代腫瘤細(xì)胞與不成熟DC體外共培養(yǎng)，用來模擬腫瘤微環(huán)境與DC的相互作用，開展以下實驗研究。 對于腫瘤周圍浸潤的DC的狀態(tài)目前還存在著爭議，但大量數(shù)據(jù)表明，腫瘤細(xì)胞通過分泌一些免疫抑制性細(xì)胞因子阻礙其周圍浸潤的DC成熟使之處于不成熟狀態(tài)；為了闡明腫瘤周圍浸潤DC的狀態(tài)，我們利用transwell系統(tǒng)用腫瘤培養(yǎng)上清對體外培養(yǎng)的不成熟DC和成熟DC分別進(jìn)行趨化，結(jié)果發(fā)現(xiàn)腫瘤培養(yǎng)上清能夠趨化大量不成熟DC，幾乎不趨化成熟DC。因此，我們將體外培養(yǎng)5天的不成熟DC與新鮮分離制備的腫瘤細(xì)胞共培養(yǎng)60h，之后用CD11c~+磁珠分離DC，檢測了誘導(dǎo)后(與腫瘤共培養(yǎng)后)的DC的表型及其在LPS刺激后的表型變化，并將之與誘導(dǎo)前的不成熟DC、不成熟DC加LPS刺激后活化成熟的DC進(jìn)行了比較。結(jié)果發(fā)現(xiàn)，與成熟DC相比，腫瘤細(xì)胞誘導(dǎo)后的DC表面分子CD86、Ia、CD11c下調(diào)，CD11b上調(diào)，而CD40、CD80的變化不大，并且在LPS刺激后表面MHCⅡ類分子和共刺激分子并沒有顯著升高，表現(xiàn)為CD11c~(low)Ia~(low)CD11b~(high)的穩(wěn)定的表型特征。 吞噬功能在一定程度上代表了DC的成熟度和功能狀態(tài)，一般認(rèn)為DC越成熟吞噬能力越弱，而抗原遞呈能力越強(qiáng)。我們進(jìn)一步分析了腫瘤細(xì)胞誘導(dǎo)形成的CD11c~(l0w)Ia_(low)CD11b~(high)DC的吞噬功能，結(jié)果發(fā)現(xiàn)該群CD11c~(low)Ia~(low)CD11b~(high)DC與不成熟DC相似，具有很強(qiáng)的吞噬能力，甚至強(qiáng)于不成熟DC的吞噬能力，即使在LPS刺激后，其仍然顯示很高的吞噬能力，但不成熟DC在LPS刺激后變成了成熟DC，其吞噬能力顯著下降。提示腫瘤細(xì)胞體外誘導(dǎo)形成的CD11c~(low)Ia~(low)CD11b~(high)DC不同于不成熟DC和成熟DC，并處于功能穩(wěn)定狀態(tài)。 從細(xì)胞因子分泌譜看，CD11c~(low)Ia~(low)CD11b~(high)DC自發(fā)分泌高量的IL-10、NO、PGE2，而IL-12的分泌量很低，LPS刺激后變化不大，進(jìn)一步提示該CD11c~(low)Ia~(low)CD11b~(high)DC處于穩(wěn)定的狀態(tài)并且可能具有下調(diào)免疫應(yīng)答的能力。 DC的重要功能是抗原遞呈能力，為了探討CD11c~(low)Ia~(low)CD11b~(high)DC的抗原遞呈能力，我們將CD11c~(low)Ia~(low)CD11b~(high)DC與OVA_(323-339)抗原肽特異性反應(yīng)的CD4~+T細(xì)胞在OVA_(323-339)抗原肽存在的條件下共培養(yǎng)，結(jié)果發(fā)現(xiàn)CD11c~(low)Ia~(low)CD11b~(high)DC刺激抗原肽特異性T細(xì)胞的能力顯著的低于成熟DC。CD11c~(low)Ia~(low)CD11b~(high)DC刺激抗原肽特異性T細(xì)胞的能力很弱，表明其本身的抗原提呈功能很弱。我們檢測了培養(yǎng)上清及T細(xì)胞胞內(nèi)細(xì)胞因子的分泌情況，結(jié)果顯示CD11c~(low)Ia~(low)CD11b~(high)DC仍然能夠刺激CD4~+T細(xì)胞分泌一定水平的IL-2和IFN-γ。 鑒于CD11c~(low)Ia~(low)CD11b~(high)DC的以上特點，我們推測該細(xì)胞可能具有負(fù)向免疫調(diào)節(jié)作用。我們將CD11c~(low)Ia~(low)CD11b~(high)DC加入到OVA_(323-339)抗原肽特異性CD4~+T／maDC／OVA_(323-339)的共培養(yǎng)體系中，結(jié)果發(fā)現(xiàn)CD11c~(low)Ia~(low)CD11b~(high)DC有效地抑制了T細(xì)胞的增殖，同樣檢測了T細(xì)胞胞內(nèi)細(xì)胞因子的分泌情況，結(jié)果表明，CD11c~(low)Ia~(low)CD11b~(high)DC仍然能夠刺激T細(xì)胞分泌一定水平的IL-2和IFN-γ。因此我們將腫瘤細(xì)胞誘導(dǎo)形成的這群CD11c~(low)Ia~(low)CD11b~(high)Dc稱為調(diào)節(jié)性DC(regulatory DC，DCreg)。 為了明確我們在體外共培養(yǎng)體系中誘導(dǎo)得到的調(diào)節(jié)性DC是否在腫瘤瘤體內(nèi)存在相應(yīng)的DC亞群，我們根據(jù)該調(diào)節(jié)性DC的表型特點，分析了腫瘤單個核細(xì)胞中CD11c~+細(xì)胞群。該調(diào)節(jié)性DC最重要的特點就是高表達(dá)CD11b、低表達(dá)CD11c及Ia，因此我們用CD11b-APC、CD11c-FITC及Ia-PE三色標(biāo)記腫瘤單個核細(xì)胞中CD11c~+細(xì)胞群，F(xiàn)ACS分析發(fā)現(xiàn)這群細(xì)胞中明顯存在一群CD11b~(high)CD11c~(low)細(xì)胞，進(jìn)一步分析CD11b~(high)CD11c~(low)細(xì)胞的Ia的表達(dá)，我們發(fā)現(xiàn)存在低、中、高連續(xù)表達(dá)的三群細(xì)胞。關(guān)于具體哪群或哪幾群細(xì)胞具有與體外腫瘤細(xì)胞共培養(yǎng)體系所誘導(dǎo)形成的調(diào)節(jié)性DC具有相似的功能特征，我們打算用FACSVantage將這三群細(xì)胞分選出來，分析它們的細(xì)胞因子分泌情況和抑制功能，最終來證實腫瘤微環(huán)境內(nèi)確實存在一群表型和功能與我們通過體外腫瘤細(xì)胞共培養(yǎng)體系所誘導(dǎo)產(chǎn)生的DCreg相似的腫瘤浸潤DC亞群。 以上研究表明，腫瘤微環(huán)境確實能夠誘導(dǎo)不成熟DC向DCreg的分化，，那么，腫瘤細(xì)胞以何種形式誘導(dǎo)了不成熟DC向DCreg的分化呢?是腫瘤細(xì)胞分泌的免疫抑制性可溶性分子，還是腫瘤細(xì)胞表面表達(dá)的抑制性膜分子，抑或是兩者共同發(fā)揮了作用?首先，我們用半定量RT-PCR檢測發(fā)現(xiàn)，3LL腫瘤細(xì)胞高表達(dá)M-CSF、TGF-β、VEGF等具有免疫抑制作用的細(xì)胞因子。為了明確3LL腫瘤細(xì)胞以何種形式誘導(dǎo)了不成熟DC向DCreg的分化，我們選擇了Transwell系統(tǒng)進(jìn)一步開展了研究。雖然多聚甲醛固定腫瘤細(xì)胞可以阻斷腫瘤細(xì)胞可溶性因子的釋放，可以用來研究腫瘤表面膜分子的作用，但由于不成熟DC具有很強(qiáng)的吞噬作用，固定腫瘤細(xì)胞會被不成熟DC吞噬，因此我們放棄了這種研究模式，采用了Transwell系統(tǒng)，Transwell系統(tǒng)可以將兩種細(xì)胞有效的隔開，避免了細(xì)胞與細(xì)胞的直接接觸，可用來研究腫瘤細(xì)胞分泌的可溶性因子的作用。我們將不成熟DC直接加入預(yù)先鋪有腫瘤細(xì)胞的24孔板中或加入到腫瘤細(xì)胞上方的Transwell小室中，比較了兩者細(xì)胞的抑制功能，結(jié)果發(fā)現(xiàn)，兩組處理的DC都能有效地抑制T細(xì)胞的增殖，且抑制的水平?jīng)]有顯著性差異，表明腫瘤細(xì)胞分泌的可溶性因子就足以使不成熟DC向DCreg轉(zhuǎn)化而具備了抑制功能。進(jìn)一步闡明哪種或哪些可溶性因子參與了不成熟DC向DCreg轉(zhuǎn)化，我們將采用中和性抗體和／或抑制劑進(jìn)行阻斷和聯(lián)合阻斷實驗。 腫瘤分泌的免疫抑制性可溶性因子構(gòu)成的腫瘤微環(huán)境，可以誘導(dǎo)進(jìn)入腫瘤的不成熟DC轉(zhuǎn)化為調(diào)節(jié)性DC，這群DC高分泌IL-10、PGE2和NO，在體外可以明顯抑制抗原特異性的CD4~+T細(xì)胞的增殖，我們推測，該群DC是否不但不具備免疫監(jiān)視和免疫防御功能，反而能夠促進(jìn)腫瘤細(xì)胞的生長和轉(zhuǎn)移呢?為了探討CD11c~(low)Ia~(low)CD11b~(high)DC是否促進(jìn)腫瘤的轉(zhuǎn)移，我們建立了3LL腫瘤的肺轉(zhuǎn)移模型，我們先用不成熟DC或DCreg尾靜脈注射小鼠，24小時后再尾靜脈注射小鼠3LL肺癌細(xì)胞，20天后處死小鼠，用墨汁灌注的方法觀察肺部的腫瘤轉(zhuǎn)移灶，結(jié)果顯示，注射DCreg組的轉(zhuǎn)移灶多于不成熟DC組。提示了該群CD11c~(low)Ia~(low)CD11b~(high)DC不但不具備免疫監(jiān)視和免疫防御功能，反而促進(jìn)腫瘤細(xì)胞的轉(zhuǎn)移。 綜上所述，腫瘤細(xì)胞可以通過組成性和／或誘導(dǎo)性分泌一些趨化因子，招引不成熟DC進(jìn)入瘤體，不成熟DC在腫瘤細(xì)胞釋放的可溶性因子作用下，進(jìn)一步分化為高分泌IL-10、PGE2和NO但低分泌IL-12的CD11c~(low)Ia~(low)CD11b~(high)調(diào)節(jié)性DC，該調(diào)節(jié)性DC能在體外抑制抗原肽特異性CD4~+T細(xì)胞的增殖反應(yīng)，并且可以在體內(nèi)促進(jìn)腫瘤轉(zhuǎn)移。本研究還初步證明了荷瘤小鼠瘤體內(nèi)可能存在相應(yīng)的調(diào)節(jié)性DC亞群，該實驗結(jié)果為腫瘤免疫逃逸提供了又一新的機(jī)制和解釋。
[Abstract]:Dendritic cell (DC) is the most powerful antigen presenting cell (Antigen-presenting cells, APC) that has been found in the body. The content of MHC class and MHC peptide complex on the surface is 10~100 times that of other APC, which can effectively induce the proliferation and response of the initial T cells (Naive) and promote the cytotoxicity of lymphoid cells. The formation of Cytotoxic T lymphocytes (CTL) and auxiliary T cells (T help cells, Th) can be seen that DC is the promoter and participant of the body's immune response. The anti-tumor immune response mediated by DC activated T cells is the dominant force in the body's anti-tumor immunity. It is reported that a dendritic like or expression surface mark is infiltrated in a number of tumor tissues. However, although the tumor cells are in this kind of cells, the tumor cells will escape the surveillance of the immune system and be overgrown and even infiltrate and metastases. Therefore, the research on the immune escape mechanism of the tumor is a hot topic in the current biomedicine. The mechanism of immune escape is not completely clear. Many studies suggest that the mechanism may be that tumor cells release a variety of inhibitory cytokines such as VEGF, TGF- beta, IL-10, M-CSF, PGE2 and so on, which cause the maturation and differentiation of DC, inhibit the ability of DC antigen presenting and weaken its ability to activate T cells, and make these DC activated signals It shows low responsiveness. As DC studies continue to deepen, various DC subgroups include the discovery of a regulatory DC with negative immunoregulation, and the function of tumor infiltrating DC becomes more complex. Is there a subgroup of DC with inhibitory function in the tumor infiltrating DC? Whether the group of DC does not possess not only immune surveillance and immune defense work, but also the group of DC On this basis, we use fresh isolated tumor cells to simulate the tumor microenvironment and the DC co incubation in vitro. The effect of tumor microenvironment on the phenotypic and functional characteristics of DC is studied to further understand the effect of tumor microenvironment on DC and the invasion of DC. The role of tumor growth and metastasis has increased the new understanding of the mechanism of tumor immune escape.
First, we selected the mouse lung cancer cell line 3LL to inoculate C57BL / 6 mice subcutaneously, replicate the tumor bearing mice model, separate the appropriate size of the tumor tissue, and grind it into a single cell suspension with collagenase, let it grow on the wall. One week later, the tumor cells with similar morphology and long growth can be obtained. The fresh isolated tumor cells are more than the swelling. The tumor cell line has a better character and can mimic the microenvironment of the tumor in the body. We have prepared GM-CSF and IL-4 for 5 days of mouse bone marrow origin CD11c~+DC. At this time, the level of Ia, CD40, CD80, CD86 on the surface of CD11c~+DC cells is relatively low and has strong phagocytosis, which can be considered as a kind of immature DC. we use fresh separation. The primary tumor cells were co cultured with immature DC in vitro to simulate the interaction between tumor microenvironment and DC.
There is still controversy about the state of DC infiltrating around the tumor, but a lot of data show that the tumor cells are immaturity by secreting some immunosuppressive cytokines that inhibit the maturation of the surrounding DC, and to clarify the state of infiltration of DC around the tumor, we use the Transwell system to use the tumor culture supernatant. The immature DC and mature DC cultured in vitro were chemotactic respectively. The results showed that the tumor culture supernatant could chemotactic a large number of immature DC and hardly chemotaxis mature DC.. Therefore, we cultured the immature DC in vitro for 5 days with the fresh isolated tumor cells to co culture 60H, then the CD11c~+ magnetic beads were used to separate DC. The phenotype of the cultured DC and its phenotypic changes after LPS stimulation were compared with the immature DC, the immature DC plus the LPS stimulation of the mature DC. The results showed that, compared with the mature DC, the surface molecules of the DC surface, which were induced by the tumor cells, were in CD86, Ia, CD11c, and up. After stimulation, the surface MHC class II molecules and costimulatory molecules did not increase significantly, showing stable phenotypic characteristics of CD11c~ (low) Ia~ (low) CD11b~ (high).
Phagocytosis, to a certain extent, represents the maturity and functional state of DC. It is generally believed that the more mature the phagocytosis of DC is, the stronger the antigen presenting ability. We further analyzed the phagocytic function of CD11c~ (L0W) Ia_ (low) CD11b~ (high) DC induced by tumor cells. Mature DC has a strong phagocytosis and even stronger than the phagocytic ability of immature DC. Even after LPS stimulation, it still shows high phagocytosis, but immature DC becomes mature DC after LPS stimulation, and its phagocytic ability decreases significantly. It suggests that CD11c~ (low) Ia~ (low) CD11b~ (high), induced by tumor cells in vitro, is different from that of no Mature DC and mature DC, and are in a stable state of function.
From the cytokine secretion spectrum, CD11c~ (low) Ia~ (low) CD11b~ (high) DC spontaneously secretes a high amount of IL-10, NO, PGE2, but the IL-12 secretion is very low, and the LPS stimulus does not change very much, further suggesting that the DC is in a stable state and may have the ability to reduce the immune response.
The important function of DC is antigen presenting ability. In order to explore the antigen presenting ability of CD11c~ (low) Ia~ (low) CD11b~ (high) DC, we co culture the CD11c~ (low) Ia~ (low) Ia~ (low) and antigen peptide specific peptide in the presence of the antigen peptide (323-339). The ability of DC to stimulate the antigenic peptide specific T cells was significantly lower than that of the mature DC.CD11c~ (low) Ia~ (low) CD11b~ (high) DC stimulating antigen peptide specific T cells, which showed that the antigen presenting function was weak. IgH) DC can still stimulate CD4~+T cells to secrete a certain level of IL-2 and IFN- gamma.
In view of the above characteristics of CD11c~ (low) Ia~ (low) CD11b~ (high) DC, we speculate that the cell may have a negative immunomodulatory function. We add CD11c~ (low) Ia~ (low) CD11b~ (low) to the co culture system of 323-339 antigen specific peptide specificity / 323-339. The proliferation of T cells was inhibited and the secretion of intracellular cytokines in T cells was also detected. The results showed that CD11c~ (low) Ia~ (low) CD11b~ (high) DC still stimulated T cells to secrete a certain level of IL-2 and IFN- gamma. Y DC, DCreg).
In order to determine whether the regulatory DC induced by our in vitro co culture system has a corresponding DC subgroup in the tumor tumor, we analyze the CD11c~+ cell group in the tumor mononuclear cells based on the phenotypic characteristics of this regulatory DC. The most important characteristic of this regulatory DC is the high expression of CD11b, the low expression of CD11c and Ia, so we use it. CD11b-APC, CD11c-FITC and Ia-PE tricolor labeled CD11c~+ cell groups in tumor mononuclear cells. FACS analysis found a group of CD11b~ (high) CD11c~ (low) cells in this group. We further analyzed the expression of CD11b~ (high) CD11c~ cells. We found three groups of cells with low, medium and high continuous expression. Which group of cells have the similar functional characteristics with the regulatory DC induced by coculture system in vitro, we intend to use FACSVantage to separate these three groups of cells, analyze their cytokine secretion and inhibitory function, and finally confirm that there is a group of phenotypes and functions in the tumor microring. Similar tumor infiltrates into DC subgroup induced by co culture system of tumor cells in vitro. DCreg
The above studies have shown that the tumor microenvironment can indeed induce the differentiation of immature DC to DCreg, so in what form does the tumor cells induce the differentiation of immature DC to DCreg, the immunosuppressive soluble molecules secreted by the tumor cells, or the inhibitory membrane molecules expressed on the surface of the tumor cells, or both of them play a role together. First, we found that 3LL tumor cells express M-CSF, TGF- beta, VEGF and other cytokines with immunosuppressive effects by semi quantitative RT-PCR detection. In order to identify the form of 3LL tumor cells to induce the differentiation of immature DC to DCreg, we chose the Transwell system to carry out a study. Cell can block the release of soluble factors of tumor cells and can be used to study the role of tumor surface mask molecules. But because immature DC has a strong phagocytosis, the fixed tumor cells will be phagocytic by immature DC. Therefore, we abandoned this research pattern, using the Transwell system, and the Transwell system can make two kinds of cells effective. Isolation, avoiding direct contact between cells and cells, can be used to study the role of soluble factors secreted by tumor cells. We add immature DC directly into 24 foramen of cancer cells or add to the Transwell cells above the tumor cells and compare the inhibitory function of the two cells. The result is that the two groups of D are treated. C can effectively inhibit the proliferation of T cells, and there is no significant difference in the level of inhibition, indicating that the soluble factors secreted by the tumor cells are sufficient to inhibit the transformation of immature DC to DCreg. Which or which kinds of soluble factors are involved in the transformation of immature DC to DCreg, we will use neutralizing antibodies and / / Blocking and joint blocking experiments were performed or depressant.
The tumor microenvironment, which is secreted by the immunosuppressive soluble factors, can induce the immature DC into the tumor to convert into regulatory DC. This group of DC hypersecreting IL-10, PGE2 and NO can obviously inhibit the proliferation of antigen specific CD4~+T cells in vitro. We speculate whether this group DC not only does not have immune surveillance and immune defense. In order to investigate whether CD11c~ (low) Ia~ (low) CD11b~ (high) DC promotes tumor metastasis, we have established a lung metastasis model of 3LL tumor. We first injected the immature DC or DCreg tail vein to mice, and then injected the mouse 3LL lung cancer cells into the tail vein in 24 small hours, and then killed the mice after 20 days. The tumor metastasis of lung was observed with the method of ink infusion. The results showed that the metastasis of DCreg group was more than that of the immature DC group. It suggested that the group CD11c~ (low) Ia~ (low) CD11b~ (high) DC not only did not have immune surveillance and immune defense, but promoted the metastasis of tumor cells.
To sum up, the tumor cells can induce immature DC into the tumor through the composition and / or inducible secretion of some chemokines. Under the action of the soluble factors released by the tumor cells, the immature DC further differentiates into the CD11c~ (low) Ia~ (low) CD11b~ (high) regulatory IL-10, PGE2 and NO, but the low secretion of IL-12. It can inhibit the proliferation of antigenic peptide specific CD4~+T cells in vitro, and can promote tumor metastasis in vivo. This study also preliminarily demonstrated that there may be a corresponding regulatory DC subgroup in tumor bearing mice, which provides another new mechanism and explanation for tumor immune escape.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2007
【分類號】：R392;R730.3

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