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05
2024
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09
Sun Yat-sen University team reveals tertiary lymphatic structure associated with tumor progression and immunotherapy response in nasopharyngeal carcinoma
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Tertiary lymphoid structures are immune cell aggregates associated with cancer prognosis, but their interaction with tumor cell aggregates is unclear.
On September 4, 2024,Sun Yat-sen UniversityBei Jin New TeamInNature Communications Published online entitled“Single-cell and spatial transcriptome analyses reveal tertiary lymphoid structures linked to tumour progression and immunotherapy response in nasopharyngeal carcinoma”The research paper,The studyrevealsTertiary lymphoid structure-associated cellular features correlate with prognosis and PD-1 blockade response, providing insights into cancer therapeutic strategies.
Using nasopharyngeal carcinoma as a model, the study analyzed the single-cell transcriptome of 343,829 cells from 77 biopsies and blood samples, and the spatially resolved transcriptome of 31,316 spots from 15 tumors to decipher their composition and interactions with tumor cell aggregates. Study identifies basic cell populations in tertiary lymphoid structures, including CXCL13+Cancer-Associated Fibroblasts, Stem Cell-Like CXCL13+CD8+T cells, and B andT follicular helper cells. Studies have shown that germinal center reactions mature plasma cells. These plasma cells are interspersed in tumor cell aggregates, promotingEBVassociated with apoptosis of malignant cells, enhancing immunotherapeutic response.CXCL13+Cancer-associated fibroblasts promote B- cell adhesion and antibody production, activating CXCL13 depleted in tumor cell aggregates+CD8+T cells.
Immune cell infiltration is a common pathological observation in cancer. Tumor cells, immune cells, stromal cells and extracellular components gather together to form tumor microenvironment (TME).The organization of these components is essential for effective antitumor immunity. Tertiary lymphoid structures (TLS) represent well-organized ectopic compartments of immune cells formed in inflammatory, infectious or neoplastic tissue. Initially, T and B cell regions were determined using immunohistochemistry (IHC) in the TLS. Subsequently, some studies have shown that in addition to the proximity of T follicular helper cells (Tfh) and follicular dendritic cells (FDC) to B cells, TLSs contain antigen-presenting cells (APCs) as regulatory factors and stromal cells as supporting basis. Recently, single-cell RNA sequencing and spatial transcriptomics studies have revealed specific cell populations of TLS in tumors, such as CXCL13 in ovarian cancer.+T helper cells, SEMA4A in squamous cell carcinoma of the head and neck+Germinal center (GC) B cells, and CXCL12 in renal cell carcinoma+Fibroblasts.These findings indicate that the composition of TLS in tumors is complex and heterogeneous from different technical perspectives, which requires further studies with larger sample sizes and cutting-edge technologies at higher resolutions.
GC is an important feature of tumor-mature TLSs and is a well-known compartment for the selective activation and expansion of B- cell clones and the generation of long-lived plasma cells.While coexistence of GC B cells with tumor-infiltrating B cells or plasma cells has been demonstrated in a variety of tumors, little is known about the dynamic characteristics of the GC response within tumors and the developmental trajectory of B cells, particularly in TLSs. A recent study has shown that GC B cells are characterized by a continuous state of gene expression across the dark-light region axis. In addition to the GC response, multiple cellular components, including lymphoid tissue inducing cells (LTI), fibroblast reticular cells (FRC), and FDC, as well as molecular processes, including LTβR signaling, adhesion molecules (VCAM1 and ICAM1), and lymphoid chemokines (CXCL13, CCL17, and CCL21), have been reported to drive TLS formation in autoimmune diseases and chronic infections. In addition, previous studies have also revealed that fibroblasts and endothelial cells coordinate the formation of TLS in mouse tumor models.In contrast, the key components that drive TLS formation in human tumors are poorly understood.
TLSs can be used with co-locatedAPCsLocal tumor antigens are processed to produce effector memory T, memory B, and plasma cells that infiltrate the tumor and participate in the antitumor response.Among them, T cells in or near TLSs upregulate the expression of pro-survival and anti-apoptotic molecular BCL-2 and inhibit the growth of melanoma.TLSAssociated plasma cells can secrete antibodies, recognize tumor-associated antigens, and through antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) promote apoptosis in malignant cells. This may explain the positive correlation between high TLS performance and high degree of tumor infiltrating immune cells, favorable patient survival, and better response to multiple human tumor immune checkpoint blockade (ICB) therapies.AlthoughTLSRelated effector T cells and B cells exhibit an anti-tumor phenotype, but how they are distributed in close spatial proximity to tumor cells and recognize them to perform their anti-tumor activity has not been characterized.
The study used nasopharyngeal carcinoma (NPC) as a model to reveal the cellular composition, formation, and function of TLS, as well as tumor progression and immunotherapy response at single-cell and spatial transcriptomic resolutions.Nasopharyngeal carcinoma is a common malignant tumor in southern China with dense immune cell infiltration. The study also evaluated the prognostic value of key TLS components on patient survival and immunotherapy response in multiple NPC cohorts.
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