BACKGROUND: Tertiary lymphoid structures (TLSs) are organized aggregates of immune cells that form postnatally in nonlymphoid tissues. TLSs are not found under physiological conditions but arise in the context of chronic inflammation, such as in autoimmune disease, chronic infection, and cancer. With few exceptions, the presence of TLSs in tumors correlates with better prognosis and clinical outcome upon immunotherapy, but, in spite of their presumed importance, the drivers of TLS formation in cancer and the contribution of these structures to intratumoral immune responses remain incompletely understood.
ADVANCES: TLSs resemble secondary lymphoid organs (SLOs) anatomically, and it was originally assumed that their formation would largely be induced by the same stimuli. However, the cell pools and signals that provide inductive stimuli for TLS formation are at least partially different. For instance, several observations suggest that tumor-specific T and B cell immunity may induce some of the molecular factors required for TLS formation and maintenance, and heterogeneity in these drivers may result in distinct TLS states. It has been speculated that TLSs recapitulate SLO functions at the inflamed tissue site, and available evidence suggests that a contribution of TLSs to the strength of tumor-specific immune responses is plausible. However, whether such a contribution primarily involves the boosting of T cell responses generated in SLOs or the development of new T and B cell reactivities remains a key unanswered question. In addition, the presence of TLSs at the tumor site may offer the possibility for the generation of qualitatively distinct immune responses. Specifically, because TLSs are not encapsulated, exposure of TLS-resident immune cells to macromolecules from the inflamed microenvironment appears to be a realistic possibility, and this could potentially sculpt the nature of intratumoral immune responses. Finally, recent studies suggest a role for TLSs in the clinical response to immune checkpoint blockade, which may make these structures attractive therapeutic targets. However, the development of such strategies should take into account the possible consequences of ectopic formation of lymphoid tissue at other body sites.
OUTLOOK: The prognostic and predictive value of TLSs in cancer has strengthened the interest in these structures as potential mediators of antitumor immunity. Although TLSs have been identified in many cancer types, the markers used to define and characterize TLSs have often varied across studies, complicating efforts to compare predictive value and to assess TLS heterogeneity between cancer types. Thus, the development of standardized approaches to measure TLS number and composition is likely to further reveal their predictive and prognostic value in different disease settings. Related to this, a more comprehensive characterization of TLSs may potentially lead to the identification of a spectrum of TLS states, based on aspects such as cellular composition, location, maturation, and function. Similar to the definition of T cell states in cancer, which has substantially improved our understanding of the role of specific T cell populations in tumor-specific immunity, the molecular definition of TLS states may help to improve their value as prognostic and predictive markers. Finally, a better appreciation of TLS function and the potential contribution of TLSs to autoimmune toxicity will be important to maximize their value as therapeutic targets.