Mathematical Modelling of Tertiary Lymphoid Structures in Cancer

NicholasLai

University of Oxford

"Mathematical Modelling of Tertiary Lymphoid Structures in Cancer"

Tertiary lymphoid structures (TLSs) are organised aggregates of immune cells that form at sites of inflammation in chronic diseases, such as cancer. It is hypothesised that, in cancer, TLSs act as local hubs for the generation and regulation of a tumour-specific immune response from inside the tumour microenvironment (TME). TLSs initially form as well-mixed aggregates of T- and B-cells and mature into organised structures consisting of an inner B-cell zone surrounded by an outer T-cell zone. The presence of TLSs correlates with positive patient outcomes in several cancer types, but the mechanisms governing their formation, maturation, and role in the antitumour response remain poorly understood. Motivated by analysis of spatial transcriptomics images of TLSs in colorectal cancer, we develop an agent-based model to investigate TLS formation, maturation, and function in cancer. We model T-cells and B-cells as discrete agents which are attracted to diffusible chemokines (CXCL13 and CCL19) produced by resident stromal cells in the TME. These interactions lead to the formation of a well-mixed lymphoid aggregate that later matures into distinct T- and B-cell zones due to the segregated expression of these chemokines. Our results identify key parameters governing TLS development and suggest conditions under which TLSs are able to control tumour growth. This framework provides a qualitative basis for understanding TLS dynamics and their potential role in cancer immunotherapy.
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