Bouloudani Théo, Pupier Guilhem, Sautès-Fridman Catherine, Fridman Wolf Herman
Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, 15 rue de l'école de Médecine, 75006 Paris, France; Équipe labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, 15 rue de l'école de médecine, 75006 Paris, France.
Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, 15 rue de l'école de Médecine, 75006 Paris, France; Équipe labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, 15 rue de l'école de médecine, 75006 Paris, France.
Immunol Lett. 2025 Dec;276:107064. doi: 10.1016/j.imlet.2025.107064. Epub 2025 Jul 30.
The discovery of Tertiary Lymphoid Structures (TLS) within tumors has reshaped our understanding of cancer immunity. Unlike the classical view that immune responses are solely initiated in lymph nodes, TLS, ectopic lymphoid aggregates resembling secondary lymphoid organs, can form in the tumor microenvironment (TME). These structures contain T cells, B cells, dendritic cells (DC) presenting antigenic peptides to T cells in the T cell zone of TLS, and follicular dendritic cells (FDC) which are stromal cells involved in the formation of germinal centers (GCs) and presenting antigens, under the form of immune complexes, to B cells. Mature TLS with GCs support B cell differentiation into antibody-producing plasma cells (PCs). Clinical studies reveal that TLS presence correlates with improved survival and response to immunotherapy across multiple cancers, including melanoma, NSCLC, and renal cell carcinoma. Notably, B cells within TLS undergo clonal expansion, somatic hypermutation, and isotype switching, generating tumor-reactive antibodies (IgG, IgA). IgG-opsonized tumor cells can be eliminated by macrophages or NK cells via antibody-dependent cell mediated cytotoxicity or apoptosis by macrophages via antibody-dependent phagocytosis whereas IgA may have dual roles, sometimes promoting immunosuppression. Additionally, B cells enhance antigen presentation to T cells, amplifying anti-tumor responses. Emerging strategies aim to induce TLS formation (e.g., via CXCL13, lymphotoxins…) or harness B cells for adoptive therapies. Future research should clarify tumor-specific antibody targets and optimize TLS induction to enhance immunotherapy. In summary, TLS and B cells are pivotal in shaping anti-tumor immunity, offering novel biomarkers and therapeutic avenues for cancer treatment.
肿瘤内三级淋巴结构（TLS）的发现重塑了我们对癌症免疫的理解。与免疫反应仅在淋巴结中启动的传统观点不同，TLS是类似于二级淋巴器官的异位淋巴聚集物，可在肿瘤微环境（TME）中形成。这些结构包含T细胞、B细胞、在TLS的T细胞区向T细胞呈递抗原肽的树突状细胞（DC），以及滤泡树突状细胞（FDC），FDC是参与生发中心（GC）形成并以免疫复合物形式向B细胞呈递抗原的基质细胞。带有GC的成熟TLS支持B细胞分化为产生抗体的浆细胞（PC）。临床研究表明，TLS的存在与多种癌症（包括黑色素瘤、非小细胞肺癌和肾细胞癌）患者生存率的提高以及对免疫疗法的反应相关。值得注意的是，TLS内的B细胞会经历克隆扩增、体细胞超突变和同种型转换，产生肿瘤反应性抗体（IgG、IgA）。IgG调理的肿瘤细胞可被巨噬细胞或NK细胞通过抗体依赖性细胞介导的细胞毒性清除，或被巨噬细胞通过抗体依赖性吞噬作用诱导凋亡，而IgA可能具有双重作用，有时会促进免疫抑制。此外，B细胞增强向T细胞的抗原呈递，放大抗肿瘤反应。新兴策略旨在诱导TLS形成（例如，通过CXCL13、淋巴毒素……）或利用B细胞进行过继性治疗。未来的研究应明确肿瘤特异性抗体靶点并优化TLS诱导以增强免疫疗法。总之，TLS和B细胞在塑造抗肿瘤免疫中起关键作用，为癌症治疗提供了新的生物标志物和治疗途径。
