脾脏微环境对肿瘤诱导髓系细胞生成和免疫特性的调控与机制

The spleen has important hematopoietic functions in the embryonic period, but those functions cease and move to the bone marrow in normal adult mammals. Emerging evidence suggests that tumors can induce extramedullary hematopoiesis (EMH) and immune alterations in the spleen, which contributes to the immune escape and disease progression of cancer. However, the regulatory mechanisms of this process remain unclear. We have recently shown that the tumor associated EMH is mediated by a unique population of hematopoietic stem/progenitor cells (HSPCs) in the spleen that arefunctionally distinct form their bone marrow counterparts. With the myeloid-biased differentiation potential, these splenic HSPCs are committed to generating immunosuppressive myeloid descendants to repress tumor immunity. Moreover, we found that splenic stromal cells were responsible for the selective recruitment and the “reprograming” of splenic HSPCs to commit tumor-promoting myelopoies, suggesting a critical mediator of the process. Based on these findings, we intend to combine experimental studies and clinical sample analysis, 1) to systemically investigate the mechanism by which the tumor influences the splenic stromal microenvironment to regulate splenic EMH and immune alterations; 2) to define novel splenic immune populations and new functions of the splenocytes that are relevant to this process; 3) to explore the clinical potential of targeting these regulatory mechanisms and critical factors in anti-tumor therapy. The results obtained from this projectwould not only provide pivotal insights into the regulatory mechanisms of splenic hematopoietic/immune functions in cancer, but may also shed light on the development of a novel strategy for cancer therapy, which restores the anti-tumor immune environments by targeting the tumor-promoting myelopoiesis at its source.

肿瘤可诱导脾脏重启造血活动（免疫细胞产生）并引起其免疫功能改变，进而介导免疫逃逸和疾病进展，但其调控机制目前尚不清楚。我们新近发现：肿瘤相关脾脏造血是由一类独特的造血前体细胞所介导，其功能与机制异于骨髓造血。脾脏基质微环境通过选择性招募并“重编程”造血前体细胞，使脾脏造血向髓系分化偏倚并定向产生免疫抑制性髓系细胞（包括MDSC和树突状细胞等）。以此为基础，本集成项目拟结合两个课题组的基础和优势，通过实验模型和临床样本来系统地研究肿瘤对脾脏微环境以及相关的造血和免疫功能的影响与调控机制；发现其中的脾脏免疫细胞新亚群和新功能；并探讨相关机制对机体抗肿瘤免疫应答以及对靶向/免疫治疗的影响。所得结果将不仅有助于我们更好的理解肿瘤调控脾脏造血/免疫属性的机制，还可为选择性干预脾脏造血/免疫反应来重建/恢复宿主抗肿瘤功能的新型治疗方案提供理论基础。符合“重大研究计划”的总体目标和集成项目指南。

肿瘤可诱导脾脏重启造血活动（免疫细胞产生）并引起其免疫功能改变，进而介导免疫逃逸和疾病进展，但其调控机制目前尚不清楚。我们发现：1、内质网应激通路调控肿瘤相关脾脏髓系细胞生成的新机制：荷瘤宿主脾脏富集了独特的GM-CSF+造血祖细胞（HPC）亚群，荷瘤脾脏的基质微环境诱导造血干/祖细胞（HSPC）的PERK活化，激活ATF4-CEBPβ内质网应激通路，生成促肿瘤MDSC前体细胞。相较于靶向肿瘤组织，选择性阻断脾脏中HSPC的PERK活化，可更有效地重建抗肿瘤免疫微环境并阻断肿瘤进展。2、代谢重塑调控组织中MDSC生成的机制以及对治疗应答的影响：在低糖情况下，肿瘤组织中MDSC生成主要依赖于未成熟髓系前体细胞中谷氨酰胺代谢水平的代偿性增强，促进了MDSC的扩增和免疫抑制功能。而组织中维甲酸代谢相关基因ADH1与维甲酸合成显著下调，可诱导MDSC产生并维持其抑制功能。肿瘤组织中MDSC数量增多可显著抑制其对免疫检查点阻断（ICB）治疗的应答。在ICB治疗后，活化T细胞可通过多种机制来诱导MDSC凋亡和失能，来进一步增强抗肿瘤免疫应答。3、构建了只需2个标记而可靠的“髓系反应评分”。该评分可反映肝癌组织中髓系反应平衡的最终状态，揭示了组织浸润抗肿瘤和促肿瘤髓系细胞亚群的变化以及免疫微环境的内涵。上述结果说明：通过从源头上改变组织髓系反应平衡，如干预髓系细胞的生成、发育、扩增与存活，可撬动组织免疫微环境向“抗肿瘤”方向倾斜并发展成为肿瘤免疫治疗的新策略。此外，脾脏髓外造血等“非经典来源”髓系细胞，罕见于正常个体，可作为潜在的“高效低毒”干预靶标。相关结果已在J Clin Invest，J Exp Med和STTT等刊物上发表标注本项目资助的论文11篇，项目负责人连续八年入选中国高被引用学者榜单。