Heterogeneity of tertiary lymphoid structures in cancer

The success of immunotherapy approaches, such as immune checkpoint blockade and cellular immunotherapy with genetically modified lymphocytes, has firmly embedded the immune system in the roadmap for combating cancer. Unfortunately, the majority of cancer patients do not yet benefit from these therapeutic approaches, even when the prognostic relevance of the immune response in their tumor entity has been demonstrated. Therefore, there is a justified need to explore new strategies for inducing anti-tumor immunity. The recent connection between the formation of ectopic lymphoid aggregates at tumor sites and patient prognosis, along with an effective anti-tumor response, suggests that manipulating the occurrence of these tertiary lymphoid structures (TLS) may play a critical role in activating the immune system against a growing tumor. However, mechanisms governing TLS formation and a clear understanding of their substantial heterogeneity are still lacking. Here, we briefly summarize the current state of knowledge regarding the mechanisms driving TLS development, outline the impact of TLS heterogeneity on clinical outcomes in cancer patients, and discuss appropriate systems for modeling TLS heterogeneity that may help identify new strategies for inducing protective TLS formation in cancer patients.