树突状细胞在抗肿瘤免疫和癌症免疫治疗中的作用
任宋雯,王鸿姣,揭祖亮*

(厦门大学生命科学学院,细胞应激生物学国家重点实验室,福建 厦门 361102)

树突状细胞; 抗原递呈; 癌症免疫; 肿瘤微环境

Roles of dendritic cell in antitumor immunity and cancer immunotherapy
REN Songwen,WANG Hongjiao,JIE Zuliang*

(State Key Laboratory of Cellular Stress Biology,School of Life Sciences,Xiamen University,Xiamen 361102,China)

dendritic cell; antigen-presentation; cancer immunotherapy; tumor microenvironment

DOI: 10.6043/j.issn.0438-0479.202111022

备注

树突状细胞(dendritic cell,DC)作为重要的抗原递呈细胞,在调节先天性免疫和获得性免疫反应中都扮演着重要的角色.近年来,关于调节DC的功能以促进抗肿瘤免疫得到了越来越多的关注.在肿瘤微环境(tumor microenvironment,TME)中,通过DC加工和递呈肿瘤相关抗原(tumor-associated antigens,TAAs)来启动抗原特异性的T细胞应答; 反之,肿瘤细胞通过释放代谢产物、细胞因子等调节TME来抑制DC的招募和功能.肿瘤组织中存在着不同亚群的DC,其功能各不相同.深入了解DC亚群在TME中的多样性和功能,可以有效提高DC的抗肿瘤免疫疗法.本文重点论述不同DC亚群在调节抗肿瘤免疫反应中的功能,以及基于DC免疫疗法的研究进展,为将来的基础和临床研究提供新的思路和策略.

Background: Dendritic cells (DCs) are a diverse group of professional antigen-presenting cells that plays an essential role in initiating innate and adaptive immune responses. Derived from a hematopoietic lineage, DCs consist of developmentally and phenotypically distinct subpopulations. Among these subsets of DCs, conventional DCs (cDCs) are specialized in antigen presentation for T cell activation. cDCs comprise two main subsets, the type 1 cDCs (cDC1s) and type 2 cDCs (cDC2s). cDC1s are specialized in presenting antigens to CD8+ T cells, whereas cDC2s are efficient in priming CD4+ T cells. In addition to cDC1s, plasmacytoid DCs develop from both common DC precursors and lymphoid progenitors, which can rapidly produce type Ⅰ interferons upon virus infection. Moreover, circulating Ly6Chigh monocytes can be differentiated into monocyte-derived DCs under inflammatory conditions and possess pro-inflammatory functions. Although DCs constitute a rare population of immune cells within tumor site and lymphoid organs, they are crucial for the mediation of antigen-specific immunity. DCs regulate immune responses or tolerance by presenting antigens to T cells, providing immunomodulatory signals and cytokine secretion.
Progress: DCs serve as professional antigen-presenting cells and play essential roles in the regulation of innate and adaptive immune responses. In the tumor microenvironment, DCs process and present tumor-associated antigens to initiate antigen-specific T cell responses. On the contrary, tumor cells produce immunosuppressive factors that can inhibit DCs’ infiltration and dampen their antitumor immunity. Herein, there is growing interest in modulating DCs’ function to induce efficient antitumor immunity. A better understanding of the diversity and functions of DCs’ subpopulations and the underlying mechanisms that regulate DCs’ function could lead to improved cancer immunotherapy. DCs have been applied to tumor immunotherapy in various kinds of preclinical or clinical trials, and DCs’ vaccination presents great potential for cancer immunotherapy. It has been shown that DCs’ vaccination is able to effectively prevent metastasis and relapse after surgical treatment of different cancers. Therefore, DCs-based immunotherapies can provide novel strategies for future clinical treatment against cancer.
Perspective: As the most potent antigen-presenting cells, DCs are able to activate naive T cells and induce antigen-specific immune responses in cancer. However, DCs are found to be suppressed or dysfunctional in the tumor microenvironment. A better understanding of how DCs are regulated in these scenarios may promote therapeutic breakthrough in clinical trials. The important question raised here is how the different subpopulations of DCs may lead to unique immune responses in the tumor microenvironment. As discussed in this review, the cDC1s are essential to induce the cross-presentation and cancer-controlling cytotoxic T cell responses, accompanied with increased survival rate in specific cancer types. On the other hand, the cDC2s are crucial for the induction of CD4+ T cell antitumor immunity. It has been well documented that DCs can enhance the efficacy of antitumor immunotherapies, but the optimal vaccination development requires further knowledge of DCs’ characters and functions. Approaches to develop the optimal DCs’ vaccination need to consider the following aspects, such as combination of conjunction with neoantigens, usage of adjuvants and enhancement of endogenous DCs’ costimulatory function. More importantly, precise and specific DCs’ targeting strategy leads to enhanced efficacy of these strategies.