Tertiary Lymphoid Structures as Mediators of Immunotherapy Response

SIMPLE SUMMARY: Tertiary lymphoid structures (TLS) are anatomic entities that are similar to, but distinct from, secondary lymphoid structures (e.g., lymph nodes) that allow for a host’s own immune system to respond in a more targeted and efficacious way. TLS are increasingly recognized as markers of prognosis in cancer patients and are now being implicated as direct mediators of immunotherapy efficacy. The inherent properties of TLS, as well as their cellular constituents, are being elucidated across tumor types, with commonalities becoming more apparent. Given the importance of TLS in a patient’s response to malignancy, the ability to induce TLS promises to be an advantageous therapeutic avenue and already appears feasible in preclinical models. ABSTRACT: Since its first application in the treatment of cancer during the 1800s, immunotherapy has more recently become the leading edge of novel treatment strategies. Even though the efficacy of these agents can at times be predicted by more traditional metrics and biomarkers, often patient responses are variable. TLS are distinct immunologic structures that have been identified on pathologic review of various malignancies and are emerging as important determinants of patient outcome. Their presence, location, composition, and maturity are critically important in a host’s response to malignancy. Because of their unique immunogenic niche, they are also prime candidates, not only to predict and measure the efficacy of immunotherapy agents, but also to be potentially inducible gatekeepers to increase therapeutic efficacy. Herein, we review the mechanistic underpinnings of TLS formation, the data on its relationship to various malignancies, and the emerging evidence for the role of TLS in immunotherapy function.