肿瘤微环境中巨噬细胞、肥大细胞活化机制的研究
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摘要
肿瘤微环境是肿瘤发生发展过程中所处的内环境,肿瘤微环境中各种成分之间的相互作用是肿瘤发生发展的决定因素。因此在进行肿瘤研究时,对于肿瘤微环境的探讨尤为重要。越来越多的证据表明,浸润到肿瘤微环境中的髓源细胞对肿瘤的生长和转移起到重要作用,其中包括巨噬细胞和肥大细胞。但其在肿瘤微环境中功能变化的机制尚不清楚。本研究旨在探讨巨噬细胞、肥大细胞在肿瘤发生发展中的作用,并初步探讨其机制。本研究分四部分,分别研究巨噬细胞和肥大细胞在肿瘤微环境中的功能变化：
第一、二部分：肿瘤微环境对巨噬细胞的影响。我们采用H22细胞和骨髓F4/80+细胞,即Gr-1+CD11b+F4/80+骨髓来源单核细胞(Bone marrow-derived monocytes, BMDMs)混合接种小鼠,或瘤内注射骨髓F4/80+细胞的方法,发现骨髓F4/80+细胞在肿瘤微环境中产生促瘤生长功能。因此我们采用了反复冻融法制备坏死肿瘤细胞释放物(molecules from necrotic tumor cells, NTC-Ms)模拟肿瘤微环境,发现NTC-Ms能促进肿瘤生长；且NTC-Ms诱导骨髓F4/80+细胞具有了MDSC表型,能抑制T细胞增殖。由于NTC-Ms中含有大量的内源性Toll样受体配体,我们采用肌肉内转染sTLR4表达载体的方法,观察是否TLR4参与了NTC-Ms对骨髓F4/80+细胞的诱导作用。结果显示：sTLR4能显著抑制肿瘤生长；当刚出现可触及肿瘤时(7d),sTLR4能使肿瘤组织内F4/80+细胞Argl基因转录水平下降,而Nos2和IL-12基因转录水平升高。我们进一步观察了肿瘤组织和肿瘤免疫治疗组织中F4/80+细胞的表型,发现均为Gr-1+CD11b+4/80+,而sTLR4同样也能增加肿瘤免疫治疗组织中F4/80+细胞Nos2和IL-12转录水平,增强4-1BBL/sPD-1肿瘤抑制作用；且更进一步降低了肿瘤免疫治疗组织中F4/80+细胞诱导T细胞凋亡的能力。以上结果表明；在肿瘤微环境中,NTC-Ms通过TLR4途径诱导巨噬细胞产生促瘤生长功能；肿瘤免疫治疗过程中,肿瘤细胞的破坏也可通过TLR4影响巨噬细胞。
第三、四部分：肿瘤微环境对肥大细胞的影响。我们采用骨髓来源肥大细胞(bone marrow-derived mast cells, BMMCs)和H22细胞混合接种或瘤内注射BMMCs的方法,发现BMMCs在肿瘤微环境中产生促瘤生长功能。由于SCF是肥大细胞分化成熟的重要因子,因此我们观察了SCF对BMMCs的作用,结果发现SCF预处理的BMMCs抑瘤作用减弱。接下来我们用NTC-Ms、TI-Ms模拟肿瘤微环境,发现NTC-Ms、TI-Ms预处理的BMMCs能促进肿瘤生长,而resveratrol、QNZ减弱了NTC-Ms的作用,提示TLR4和SCF可能参与了NTC-Ms对BMMCs的诱导作用。因此,我们首先证明了NTC-Ms和TI-Ms中含有功能性SCF,然后用SCF和TLR4的特异性配体LPS协同刺激BMMCs,发现BMMCs产生了促瘤生长功能；而在瘤内注射BMMCs的模型中,肌肉内转染sTLR4表达载体,则减弱了肥大细胞的促瘤功能,进一步说明SCF和TLR4配体增强了肥大细胞促瘤生长潜能。为了明确SCF和TLR4配体发挥作用的机制,我们观察了不同处理条件下,BMMCs脱颗粒、IL-10表达和对肿瘤生长的影响。结果显示,SCF/LPS、NTC-Ms和TI-Ms均能抑制肥大细胞自发脱颗粒,但不影响VEGF和PDGF的表达；且SCF/LPS、NTC-Ms和TI-Ms均能刺激BMMCs表达IL-10; resveratrol、wortmannin和QNZ可抑制NTC-Ms的作用。进一步研究发现,SCF和TLR4配体抑制肥大细胞脱颗粒和产生IL-10的功能涉及Tyr216-GSK3β磷酸化,其磷酸化抑制剂LiCl抑制肿瘤生长,消除了NTC-Ms、SCF/LPS对BMMCs自发性脱颗粒的抑制作用,且减弱了NTC-Ms、SCF/LPS诱导的BMMCs IL-10表达水平。以上结果表明,肿瘤微环境中的SCF和TLR4配体共同作用于肥大细胞,通过调节PI3K、NF-κB和Tyr216-GSK3β的磷酸化,调控肥大细胞脱颗粒和细胞因子释放,增强其促瘤生长功能。
综上所述,本研究探讨了肿瘤微环境对巨噬细胞和肥大细胞功能的影响,并初步探讨了其机制,为肿瘤的靶向治疗提供了理论依据。
The tumor growth is regulated by a precise balance between pro-and anti-tumorigenic effects, stimulated by the tumor cells themselves and their microenvironment. The role of the tumor microenvironment during the study of carcinogenesis is now realized to be important. There is a growing acceptance that bone marrow-derived myeloid cells infiltrating into the tumor microenvironment, including macrophages and mast cells, can play an important role in tumor growth. But the true role of them in tumor remains to be elucidated. This study aims to reveal the effect of macrophages or mast cells on tumor growth. This experiment is subdivided into four parts:
PartⅠ,ⅡEffect of macrophages on tumor growth. To observe the effect of Gr-1+CDllb+F4/80+ BMDMs on tumor growth, Gr-1+CDllb+F4/80+ BMDMs prepared from bone marrow cells of naive mice were co-inoculated with H22 cells (co), or injected into palpable tumor (in). The coinoculation of BMDMs with tumor cells suppressed tumor growth, whereas the injection of BMDMs into palpable tumor promoted the growth of tumor. Tumor growth could be significantly promoted by continuous i.p. injection of NTC-Ms starting 10d before tumor inoculation. F4/80+ myeloid cells induced by continuous i.p. injection of NTC-Ms reduced the T cell proliferation. The effect of sTLR4 on tumor growth was observed. In palpable tumor, sTLR4 decreased the transcription of Argl gene and increased the transcription of the IL-12 gene. And sTLR4 significantly suppressed the growth of tumors. F4/80+ cells in tumor immunotherapy microenvironment were mainly Gr-1+CDllb+. The sTLR4 increased transcription levels of Nos2 and IL-12 relative to those of Argl and IL-10 in F4/80+cells in the microenvironment of tumor immunotherapy, further reduced the apoptosis inducing capacity of F4/80+ cells and enhanced the suppressive effect of 4-BBL/sPD-1 on tumor growth.
PartⅢ,ⅣEffect of mast cells on tumor growth. To observe the effect of mast cells on tumor growth, BMMCs prepared from bone marrow cells of naive mice were co-inoculated with H22 cells (co), or injected into palpable tumor (in). The coinoculation of BMMCs with tumor cells suppressed tumor growth, whereas the injection of BMMCs into palpable tumor promoted the growth of tumor. In co-inoculation test, the suppress effect of BMMCs on tumor growth was attenuated by SCF, and BMMCs pre-treated with NTC-Ms or TI-Ms promoted tumor growth, which can be suppressed by resveratrol or QNZ. Functional SCF in NTC-Ms or TI-Ms were detected. In intra-tumor injection test, sTLR4 reduced tumor-promoting effect of BMMCs. NTC-Ms, TI-Ms or SCF/LPS could suppress spontaneous degranulation of mast cells but not secretion of VEGF and PDGF. And SCF/LPS, NTC-Ms or TI-Ms treatment increased the expression of IL-10 in BMMCs, but resveratrol, wortmannin or QNZ suppressed the effect of SCF/LPS, NTC-Ms and TI-Ms on BMMCs. Inhibition effect of SCF/LPS, NTC-Ms or TI-Ms on BMMCs degranulation were eliminated by LiCl. IL-10 expression in BMMCs was suppressed by LiCl. Tumor growth could be suppressed if mice received i.p. injection of LiCl. In co-inoculation test, when BMMCs were pre-treated with LiCl,.the percentage of CD8+ T cells in tumor increased, IL-10 expression in the tissues at inoculation sites decreased, tumor growth were suppressed.
In summary, we investigate the influence of tumor microenvironment on macrophages and mast cells, and explore the mechanism of functional switch. This study would provide scientific rational for the next step of target immune therapy.
第一、二部分：肿瘤微环境对巨噬细胞的影响。我们采用H22细胞和骨髓F4/80+细胞,即Gr-1+CD11b+F4/80+骨髓来源单核细胞(Bone marrow-derived monocytes, BMDMs)混合接种小鼠,或瘤内注射骨髓F4/80+细胞的方法,发现骨髓F4/80+细胞在肿瘤微环境中产生促瘤生长功能。因此我们采用了反复冻融法制备坏死肿瘤细胞释放物(molecules from necrotic tumor cells, NTC-Ms)模拟肿瘤微环境,发现NTC-Ms能促进肿瘤生长；且NTC-Ms诱导骨髓F4/80+细胞具有了MDSC表型,能抑制T细胞增殖。由于NTC-Ms中含有大量的内源性Toll样受体配体,我们采用肌肉内转染sTLR4表达载体的方法,观察是否TLR4参与了NTC-Ms对骨髓F4/80+细胞的诱导作用。结果显示：sTLR4能显著抑制肿瘤生长；当刚出现可触及肿瘤时(7d),sTLR4能使肿瘤组织内F4/80+细胞Argl基因转录水平下降,而Nos2和IL-12基因转录水平升高。我们进一步观察了肿瘤组织和肿瘤免疫治疗组织中F4/80+细胞的表型,发现均为Gr-1+CD11b+4/80+,而sTLR4同样也能增加肿瘤免疫治疗组织中F4/80+细胞Nos2和IL-12转录水平,增强4-1BBL/sPD-1肿瘤抑制作用；且更进一步降低了肿瘤免疫治疗组织中F4/80+细胞诱导T细胞凋亡的能力。以上结果表明；在肿瘤微环境中,NTC-Ms通过TLR4途径诱导巨噬细胞产生促瘤生长功能；肿瘤免疫治疗过程中,肿瘤细胞的破坏也可通过TLR4影响巨噬细胞。
第三、四部分：肿瘤微环境对肥大细胞的影响。我们采用骨髓来源肥大细胞(bone marrow-derived mast cells, BMMCs)和H22细胞混合接种或瘤内注射BMMCs的方法,发现BMMCs在肿瘤微环境中产生促瘤生长功能。由于SCF是肥大细胞分化成熟的重要因子,因此我们观察了SCF对BMMCs的作用,结果发现SCF预处理的BMMCs抑瘤作用减弱。接下来我们用NTC-Ms、TI-Ms模拟肿瘤微环境,发现NTC-Ms、TI-Ms预处理的BMMCs能促进肿瘤生长,而resveratrol、QNZ减弱了NTC-Ms的作用,提示TLR4和SCF可能参与了NTC-Ms对BMMCs的诱导作用。因此,我们首先证明了NTC-Ms和TI-Ms中含有功能性SCF,然后用SCF和TLR4的特异性配体LPS协同刺激BMMCs,发现BMMCs产生了促瘤生长功能；而在瘤内注射BMMCs的模型中,肌肉内转染sTLR4表达载体,则减弱了肥大细胞的促瘤功能,进一步说明SCF和TLR4配体增强了肥大细胞促瘤生长潜能。为了明确SCF和TLR4配体发挥作用的机制,我们观察了不同处理条件下,BMMCs脱颗粒、IL-10表达和对肿瘤生长的影响。结果显示,SCF/LPS、NTC-Ms和TI-Ms均能抑制肥大细胞自发脱颗粒,但不影响VEGF和PDGF的表达；且SCF/LPS、NTC-Ms和TI-Ms均能刺激BMMCs表达IL-10; resveratrol、wortmannin和QNZ可抑制NTC-Ms的作用。进一步研究发现,SCF和TLR4配体抑制肥大细胞脱颗粒和产生IL-10的功能涉及Tyr216-GSK3β磷酸化,其磷酸化抑制剂LiCl抑制肿瘤生长,消除了NTC-Ms、SCF/LPS对BMMCs自发性脱颗粒的抑制作用,且减弱了NTC-Ms、SCF/LPS诱导的BMMCs IL-10表达水平。以上结果表明,肿瘤微环境中的SCF和TLR4配体共同作用于肥大细胞,通过调节PI3K、NF-κB和Tyr216-GSK3β的磷酸化,调控肥大细胞脱颗粒和细胞因子释放,增强其促瘤生长功能。
综上所述,本研究探讨了肿瘤微环境对巨噬细胞和肥大细胞功能的影响,并初步探讨了其机制,为肿瘤的靶向治疗提供了理论依据。
The tumor growth is regulated by a precise balance between pro-and anti-tumorigenic effects, stimulated by the tumor cells themselves and their microenvironment. The role of the tumor microenvironment during the study of carcinogenesis is now realized to be important. There is a growing acceptance that bone marrow-derived myeloid cells infiltrating into the tumor microenvironment, including macrophages and mast cells, can play an important role in tumor growth. But the true role of them in tumor remains to be elucidated. This study aims to reveal the effect of macrophages or mast cells on tumor growth. This experiment is subdivided into four parts:
PartⅠ,ⅡEffect of macrophages on tumor growth. To observe the effect of Gr-1+CDllb+F4/80+ BMDMs on tumor growth, Gr-1+CDllb+F4/80+ BMDMs prepared from bone marrow cells of naive mice were co-inoculated with H22 cells (co), or injected into palpable tumor (in). The coinoculation of BMDMs with tumor cells suppressed tumor growth, whereas the injection of BMDMs into palpable tumor promoted the growth of tumor. Tumor growth could be significantly promoted by continuous i.p. injection of NTC-Ms starting 10d before tumor inoculation. F4/80+ myeloid cells induced by continuous i.p. injection of NTC-Ms reduced the T cell proliferation. The effect of sTLR4 on tumor growth was observed. In palpable tumor, sTLR4 decreased the transcription of Argl gene and increased the transcription of the IL-12 gene. And sTLR4 significantly suppressed the growth of tumors. F4/80+ cells in tumor immunotherapy microenvironment were mainly Gr-1+CDllb+. The sTLR4 increased transcription levels of Nos2 and IL-12 relative to those of Argl and IL-10 in F4/80+cells in the microenvironment of tumor immunotherapy, further reduced the apoptosis inducing capacity of F4/80+ cells and enhanced the suppressive effect of 4-BBL/sPD-1 on tumor growth.
PartⅢ,ⅣEffect of mast cells on tumor growth. To observe the effect of mast cells on tumor growth, BMMCs prepared from bone marrow cells of naive mice were co-inoculated with H22 cells (co), or injected into palpable tumor (in). The coinoculation of BMMCs with tumor cells suppressed tumor growth, whereas the injection of BMMCs into palpable tumor promoted the growth of tumor. In co-inoculation test, the suppress effect of BMMCs on tumor growth was attenuated by SCF, and BMMCs pre-treated with NTC-Ms or TI-Ms promoted tumor growth, which can be suppressed by resveratrol or QNZ. Functional SCF in NTC-Ms or TI-Ms were detected. In intra-tumor injection test, sTLR4 reduced tumor-promoting effect of BMMCs. NTC-Ms, TI-Ms or SCF/LPS could suppress spontaneous degranulation of mast cells but not secretion of VEGF and PDGF. And SCF/LPS, NTC-Ms or TI-Ms treatment increased the expression of IL-10 in BMMCs, but resveratrol, wortmannin or QNZ suppressed the effect of SCF/LPS, NTC-Ms and TI-Ms on BMMCs. Inhibition effect of SCF/LPS, NTC-Ms or TI-Ms on BMMCs degranulation were eliminated by LiCl. IL-10 expression in BMMCs was suppressed by LiCl. Tumor growth could be suppressed if mice received i.p. injection of LiCl. In co-inoculation test, when BMMCs were pre-treated with LiCl,.the percentage of CD8+ T cells in tumor increased, IL-10 expression in the tissues at inoculation sites decreased, tumor growth were suppressed.
In summary, we investigate the influence of tumor microenvironment on macrophages and mast cells, and explore the mechanism of functional switch. This study would provide scientific rational for the next step of target immune therapy.
引文
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