免疫原性细胞死亡与三级淋巴结构

Fig. 1 | Key features of primary lymphoid organs, secondary lymphoid organs and tertiary lymphoid structures. Comparison of the cellular and tissue architecture of primary lymphoid organs, secondary lymphoid organs and tertiary lymphoid structures (TLSs). Primary lymphoid organs such as the thymus (left) and bone marrow (not depicted) are developmentally programmed immune organs responsible for lymphocyte development and maturation. By contrast, secondary lymphoid organs, such as lymph nodes (centre) and spleen (not depicted), are specialized immune structures that initiate and coordinate adaptive immune responses. Tertiary lymphoid structures (right) arise ectopically within peripheral tissues in response to chronic inflammatory cues and locally orchestrate immune responses in settings such as cancer, infection, autoimmunity and transplantation. Differences in structural organization, capsule formation, high endothelial venule presence and key molecular pathways involved in tissue development and maintenance for these structures are summarized in Table 1. DC, dendritic cell; FDC, follicular dendritic cell.

Fig. 2 | Formation of tertiary lymphoid structures. Parts 1–4 depict the main steps involved in the formation of tertiary lymphoid structures (TLSs). Initially in the process of TLS formation (part 1), inflammation triggers the infiltration of innate immune cells (such as macrophages and dendritic cells) and promotes the release of pro-inflammatory cytokines (for example, tumour necrosis factor (TNF) and IL-6), activating stromal cells. Following this stromal activation (part 2), chemokine secretion (CCL19, CCL21 and CXCL13) promotes lymphocyte recruitment via high endothelial venule (HEV)-like vessels. Next (part 3), lymphocytes organize into T cell zones and B cell zones around fibroblastic reticular cells (FRCs) and follicular dendritic cells (FDCs), and finally (part 4), mature TLSs form. Mature TLSs feature segregated B cell follicles with germinal centres, T cell-dependent areas that contain dendritic cells, and peripheral HEV-like vessels, where plasma cell egress. These TLSs support adaptive immune responses in the tissue.

Fig. 3 | A two-step model of how immunogenic cell death induces tertiary lymphoid structure formation. In step 1 (top), damage-associated molecular patterns (DAMPs), such as extracellular ATP and high-mobility group box 1 (HMGB1), as well as cGAMP released by cancer cells undergoing immunogenic cell death (ICD) activate dendritic cells (DCs), myeloid cells and endothelial cells, leading to cGAS–STING signalling and production of type I interferons (IFN), TNF, IL-1 family cytokines and chemokines including CCL5, CCL19 and CCL21. This inflammatory milieu promotes endothelial activation, vascular normalization with high endothelial venule (HEV)-like features (VCAM1 and PNAd expression), and recruitment of CCR7+ lymphocytes, resulting in loose perivascular T cell– DC aggregates within the tumour stroma. In step 2 (bottom), ICD-associated IL-33 and lymphotoxin signals provided by activated T cells, B cells and group 2 innate lymphoid cells (ILC2s) engage lymphotoxin β receptor (LTβR) on fibroblasts, driving their activation and upregulation of ICAM1 as well as the expression of the lymphoid chemokines CCL19, CCL21, CCL12 and CXCL13. Sustained production of these mediators, together with ongoing type I IFN, TNF and IL-1 family cytokine signalling, consolidates the loose aggregates into organized, mature tertiary lymphoid structures (TLSs) that contain segregated lymphocyte zones and specialized vasculature.