Mouse Models Enable the Functional Investigation of Tertiary Lymphoid Structures in Cancer

Tertiary lymphoid structures (TLSs) are organized lymphoid aggregates that form within nonlymphoid tissue, including tumors, in response to persistent inflammatory stimulation. In cancer patients, TLSs are generally associated with positive clinical outcomes. However, the cellular composition and spatial distribution of TLSs can vary depending on the underlying disease state, complicating interpretations of their prognostic significance. Murine models are indispensable for providing a deeper insight into the mechanisms involved in TLS formation and function. Studies using these models can complement current clinical efforts to characterize TLSs via genetic sequencing and histopathology of human samples. Several features of TLSs resemble that of secondary lymphoid organs (SLOs). Consequently, vascular system components and structural support elements are important for TLS formation and maintenance. Furthermore, TLSs in different tissue environments can exhibit distinct characteristics, necessitating careful consideration when selecting mouse models for study. Herein, we discuss critical aspects to consider when modeling TLSs and describe recent findings of TLS studies in the mouse lung and intestinal gut environments as examples to highlight the importance of considering tissue-specific regulatory mechanisms for TLSs. In this chapter, we also summarize the mechanistic insights derived from murine models on the formation and function of TLSs, which may translate to the future therapeutic modulation of TLS in disease.