基于间充质干细胞的肿瘤免疫反应调控机制和对抗新策略

Cancer is a leading cause of death. Tumor progression is associated with cancer cell immortality, metastases, and resistance to chemotherapy and radiotherapy. In addition to the uncontrolled tumor cell growth, emerging evidence reveals that immune responses play important roles in the progression of incipient neoplasia, late-stage tumors, and metastases. Our recent study found that the orchestration of mesenchymal stem cells (MSCs), immune cells, and inflammatory factors resulted in a tumor immunosuppressive environment, whereby facilitating tumor growth. Moreover, our preliminary data also revealed that dysregulation of p53 expression in MSCs (not in tumor cells) can promote tumor growth through downregulating T cell activation. These studies, therefore, shed new light on the pivotal role of MSCs in the formation of tumor immunosuppressive status, however, the detailed mechanisms are not clear. Here we hypothesize that MSCs can specifically migrate into tumor and become immunosuppressive and tumor promoting under the influence of the inflammatory microenvironment. We propose 4 specific aims to test this hypothesis. Based on the crosstalk between MSCs and immune responses, we will determine 1) the mechanisms of inflammatory cytokines in modulating the immunoregulatory properties of MSCs in tumor sites; 2) the role of tumor suppressor gene in MSCs in modulating the immune response status in tumor sites; 3) the effects of chemotherapeutic reagents or radiation treated MSCs on the formation of immunosuppressive tumor microenvironment; 4) the potential MSC-based tumor therapy. We believe that the completion of this study will provide not only the critical information for understanding of the formation of tumor cell evading immunosuppressive microenvironment, but also for designing new anti-cancer strategies.

癌症的发生、转移和对放化疗抵抗是导致患者死亡的主要原因。它的形成、进展和转归不只涉及肿瘤细胞自身的恶性增殖和转移，其与肿瘤免疫反应状态密切相关。我们的研究发现，间充质干细胞（MSC）与免疫的交互作用促进肿瘤免疫耐受状态的形成，调控肿瘤生长。此外，抑癌基因突变的MSC也通过调控免疫反应影响肿瘤生长。究竟肿瘤免疫抑制状态的塑造如何受MSC的调控仍尚不清楚。因此，我们提出假设内因、外因调控的MSC在塑造肿瘤免疫耐受和调控肿瘤病理进程中发挥重要作用。围绕这一假设，本项目拟探讨1）炎症性细胞因子塑造MSC调控肿瘤免疫特性的多样性；2）抑癌基因缺陷的MSC调控肿瘤免疫耐受的作用和机制；3）放疗或化疗处理的MSC对肿瘤免疫反应的调节作用和机制；4）探索以MSC为靶点的肿瘤治疗新策略。我们的研究以MSC为视角，多层次分析肿瘤发生、发展和转归的免疫逃逸机制，提出肿瘤病理机制的新概念，形成治疗肿瘤的新策略。

肿瘤被认为是永远无法愈合的创伤，其在发生伊始就主动募集间充质干细胞（mesenchymal stem/stromal cells, MSCs）参与构建肿瘤微环境。基于间充质干细胞与肿瘤细胞、免疫细胞、血管内皮细胞等的交互作用，本项目重点研究肿瘤MSCs的形成机制和免疫调节特性，特别是炎症调控MSCs的肿瘤免疫调节特性的多样性及其在肿瘤发展中的作用机制，并以此为基础，探索肿瘤免疫调控新策略。本项目研究发现：1）肿瘤细胞分泌的“外泌体”可以诱导MSCs形成肿瘤MSCs，通过表达大量的CCR2配体，促进肿瘤免疫耐受环境的形成；2）通过比对肿瘤MSCs、TNFα处理MSCs以及骨髓MSCs的趋化因子表达谱，发现肿瘤MSCs和TNFα处理MSCs表达丰富的CCR5配体、CCR2配体以及CXCR2配体，招募中性粒细胞，促进乳腺癌细胞的远端转移；3）研究发现肿瘤MSCs调控乳腺癌细胞的远端转移依赖于微环境中TGFβ对MSCs的调控。TGFβ可以下调MSCs中CXCL12，其中低水平的CXCL12促使肿瘤细胞维持高水平CXCR7表达，促进肿瘤细胞的远端转移；4）明确MSCs塑造肿瘤免疫微环境的核心分子，发现MSCs免疫调节作用的可塑性及其调控机制依赖于吲哚胺，2-3，双加氧酶（人）和一氧化氮合成酶（鼠）；5）通过分析MSCs免疫抑制分子的交互作用，发现炎症因子诱导人MSCs中吲哚胺，2-3，双加氧酶的表达，该酶通过其调控的代谢产物犬尿氨酸调控TSG6表达，并且影响中性粒细胞、巨噬细胞等在炎症部位的浸润；6）基于MSCs免疫调节可塑性，证明I型干扰素提高抗肿瘤免疫反应的核心机制，形成了新的靶向肿瘤免疫微环境的新策略；7）受邀在Nature Reviews Drug Discovery上发表综述，系统地总结了肿瘤MSCs的特性，及其在肿瘤免疫微环境塑造、肿瘤生长与转移、化疗抵抗和免疫治疗中的作用及机制，为靶向性调控肿瘤MSCs，有效控制和治疗肿瘤提供了新的策略和方向。带有本项目资助的文章13篇，主要发表在Nature Reviews Drug Discovery, Cell Reports, PNAS, Oncogene等国际著名学术期刊上。申请专利3项，授权1项中国专利，1项美国专利。培养博士研究生7名，博士后2名。