Abstract
Tertiary lymphoid structures (TLSs) develop in non-lymphatic tissue in chronic inflammation and cancer. TLS can mature to lymph node (LN) like structures with germinal centers and associated vasculature. TLS neogenesis in cancer is highly varied and tissue dependent. The role of TLS in adaptive antitumor immunity is of great interest. However, data also show that TLS can play a role in cancer metastasis. The importance of lymphatics in cancer distant metastasis is clear yet the precise detail of how various immunosurveillance mechanisms interplay within TLS and/or draining LN is still under investigation. As part of the tumor lymphatics, TLS vasculature can provide alternative routes for the establishment of the pre-metastatic niche and cancer dissemination. The nature of the cytokine and chemokine signature at the heart of TLS induction can be key in determining the success of antitumor immunity or in promoting cancer invasiveness. Understanding the biochemical and biomechanical factors underlying TLS formation and the resulting impact on the primary tumor will be key in deciphering cancer metastasis and in the development of the next generation of cancer immunotherapeutics.
Highlights
Tertiary lymphoid structures (TLSs) develop postnatally in non-lymphoid tissue following a prolonged inflammatory state
The role of TLS in cancer immunity and immunotherapy has been of major interest lately as multiple studies in cancer patients correlated the presence of mature, germinal center containing TLSs with response to immunotherapy (Cabrita et al, 2020; Helmink et al, 2020)
Even though the role of lymphatics in metastatic spread is undeniable, recent data clearly show that the draining lymph node (LN) is not responsible for seeding the entirety of distant metastases
Summary
Tertiary lymphoid structures (TLSs) develop postnatally in non-lymphoid tissue following a prolonged inflammatory state. Melanoma cells suffered far lower levels of ferroptosis-induced oxidative stress in the lymph than the blood as they incorporated oleic acid in triacylglycerols of ApoB + vesicles into their plasma membrane which even permitted them to resist oxidative stress in the distant organ and circulation after exiting the lymphatics (Ubellacker et al, 2020) While this in-vivo data showed a clear role for lymphatics and in particular via LNs in establishing distant metastasis, LNs alone cannot tell the whole story of distant metastasis. A possible role for TLS in metastasis would mainly stem from the fact that as the TLS develops it promotes ectopic lymphangiogenesis and HEV formation This de novo vasculature has been shown to play a key role in anti-tumoral immunity in most cancers but this does not exclude a potential role in acting as a route of spread for tumor cells to reach either
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