Manipulating tertiary lymphoid structures to modulate disease outcome

Chronic inflammation drives the formation of tertiary lymphoid structures (TLS) – a spectrum of ectopic lymphoid cell aggregates that can form within many tissues. Clinical observations correlate TLS to both pathological and beneficial adaptive immune responses in different disease states. However, much of our understanding of how TLS form is assumed from embryonic secondary lymphoid tissue development, despite clear differences in tissue sites, timing and cellular players involved. We still lack clear understanding of the molecular cues driving TLS formation across diverse tissues and inflammatory contexts. Furthermore, exactly how these tissue niches alter local immune function and disease progression remains to be determined. Our over-arching hypothesis is that TLS can be manipulated to improve disease outcome. We will test this and answer: 1_How does immune/stromal cell crosstalk generate a spectrum of TLS in cancer? 2_Are there universal features in TLS across different pathologies? 3_What immune functions are supported by the spectrum of TLS maturation states? 4_Can we exploit key features of TLS to modulate immune function in disease? Here, three research groups with distinct, but highly complementary expertise and experimental approaches will collaborate to discover why and how TLS form and the mechanisms through which they support specific immune functions.