Tertiary Lymphoid Structures and Immunotherapy: Challenges and Opportunities

免疫疗法 医学 免疫学 免疫系统
作者
Nancy H. Ruddle
出处
期刊:Methods in molecular biology [Springer Science+Business Media]
卷期号:: 299-312
标识
DOI:10.1007/978-1-0716-4184-2_16
摘要

Tertiary lymphoid structures (TLS) are accumulations of lymphoid cells that arise in ectopic sites through the process of lymphoid neogenesis in chronic inflammation in autoimmunity, microbial infections, organ rejection, aging, and cancer. Their cellular composition and function and regulation via members of the lymphotoxin (LT)/tumor necrosis factor (TNF) family resemble that of secondary lymphoid organs (SLOs). Tumor-associated (TA)-TLS can be associated with favorable clinical outcomes. Immunotherapy in the form of immune checkpoint inhibitors (ICI) has contributed to tremendous advances in cancer therapy. However, ICI are effective in only some tumors, can give rise to resistance, and can precipitate immune-related adverse events (irAEs), many of which appear to have hallmarks of autoimmunity and can resemble TLS. TA-TLS correlate with a positive response to immunotherapy, but they can also be associated with susceptibility to irAEs, suggesting that TA-TLS in combination with ICI could lead to uncontrolled autoimmunity. The tumor environment can be manipulated to ensure that, not only the number of TLS, but also their cellular composition and appropriate function allow for judicious combinations of TLS and immunotherapy that can synergize and contribute to better outcomes with a minimum of destructive irAEs. Strategies include directed delivery of lymphoneogenic cytokines and chemokines or vascular growth factors directly, via transgenes or via adenovirus vectors.
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