乳腺癌诱导造血前体细胞动员和分化为MDSC的调控机制及临床意义

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells and myeloid progenitor cells that negatively regulate immune responses in various conditions, including chronic infectious diseases, sepsis, trauma, autoimmune diseases, transplantation and tumors. MDSC are accumulated in tumor tissues, exerting their suppressive effects and promoting disease progression. However, the nature and underlying regulatory mechanism of MDSC are still largely unknown, in particular for human. We recently observed that breast cancer could induce the down-regulation of key chemokine CXCL12 in the bone marrow of mice, which lead to the migration of hematopoietic stem and progenitor cells (HSPC) to the spleen. There is a large amount of HSPC accumulated in breast cancer tissues, and these HSPC exhibited higher proliferative potential than MDSC. We also found that several cytokines produced by various tumors could induce the differentiation of HSPC into functional MDSC. These findings suggest that the tumor induces the mobilization of HSPC into peripheral blood and tumor tissues, which is likely to be a new mechanism of the accumulation of MDSC in cancer patients. Based on these findings, we will combine the clinical sample analysis and experimental studies to: 1) dissect the underlying mechanisms that regulate the ability of bone marrow to retain HSPC in tumor bearing hosts; 2) screen and define the key factors/signaling molecules that regulate the mobilization and differentiation of HSPC into MDSCs; 3) dissect the feasibility of targeted HSPC-MDSC therapy. The results obtained from this project will not only reveal the molecular mechanisms by which tumor induce the mobilization of HSPC, but also provide the molecular basis for the generation of MDSC as novel target for cancer prevention and cure.

髓源免疫抑制细胞（MDSC）是近年发现的具有未成熟分化特性及很强免疫抑制功能的髓系细胞。在肿瘤中MDSC数量显著增加并通过多种途径诱导免疫耐受和疾病进展。我们前期发现：乳腺癌诱导小鼠骨髓中造血前体细胞（HSPC）保留分子CXCL12下调，骨髓保留HSPC能力下降，引起HSPC向外周（脾脏）迁移；肿瘤组织中存在大量HSPC聚集且相对MDSC具有更高的增殖潜能；肿瘤来源的细胞因子可诱导HSPC分化为MDSC。提示：肿瘤诱导骨髓中HSPC向外周及肿瘤动员，很可能是肿瘤中MDSC产生的新机制。以此为基础，本课题拟以乳腺癌为模型，探讨肿瘤诱导骨髓保留HSPC能力降低、调控HSPC向肿瘤动员和分化为MDSC的关键分子；明确肿瘤调控该分子表达的机制；结合小鼠模型，探讨靶向HSPC-MDSC治疗的可行性。为探讨通过“恢复”骨髓保留HSPC能力及调控肿瘤中MDSC的产生来“重建”机体的免疫功能提供理论基础。

髓源免疫抑制细胞（MDSC）是近年发现的具有未成熟分化特性及很强免疫抑制功能的髓系细胞。在肿瘤中MDSC数量显著增加并通过多种途径诱导免疫耐受和疾病进展。我们通过建立的乳腺癌小鼠模型，研究发现：随着肿瘤的进展，MDSC的来源造血前体细胞（HSPC）发生了从骨髓到外周的迁移。荷瘤小鼠骨髓细胞中，招募和保留HSPC分子的表达水平，包括CXCL12、KitL、VCAM1和ANGPT1，发生了显著下调。同时，骨髓微环境中间充质干细胞（MSC）也明显减少，导致骨髓保留HSPC能力下降。更进一步，我们发现这些动员的HSPC大量富集于肿瘤组织中并同时能在体内检测大量的MDSC。体外研究也显示这些HSPC具有较强的增殖能力并且可以在肿瘤微环境中产生具有免疫抑制功能的MDSC。目前已知G-CSF和GM-CSF是重要的髓系分化相关的细胞因子，在多种肿瘤中被报道可以促进MDSC的产生。我们通过机制研究发现：谷氨酰胺饥饿可通过激活IRE1α-JNK通路促进乳腺癌细胞表达G-CSF和GM-CSF，提示谷氨酰胺代谢在肿瘤中MDSC的产生起了重要作用。同时，生存分析显示乳腺癌患者肿瘤中G-CSF高表达与总生存成负相关。最后，体内的PD-L1药物实验发现，通过BPTES抑制MDSC的谷氨酰胺代谢，可以增加了肿瘤中CD8+、IFN-γ+和GranzymeB+T细胞的比例，减少MDSC的产生来逆转ICB治疗的耐药性。本研究阐明了乳腺癌肿瘤组织中MDSC的来源和产生的机制，为靶向MDSC的治疗策略提供了新的靶标。