Tertiary lymphoid structures in colorectal cancer - organization and immune cell interactions

Tertiary lymphoid structures (TLS), formerly recognized as Crohn's-like structures, serve as crucial biomarkers for evaluating the progression of colorectal cancer (CRC). Understanding their spatial distribution, cellular composition, and interactions within CRC is paramount for comprehending the immune response in the tumor microenvironment (TME). TLS are comprised of a T-cellular compartment and a B-cellular compartment, the latter encompassing follicular dendritic cells (FDCs), high endothelial venules (HEVs), and lymphatic vessels. While T helper cells predominate in cancer TLS, the specific functions of their subpopulations remain inadequately understood. Notably, T follicular helper (Tfh) cells play a central role in the activation of CD8⁺ T cells, and both Tfh cells and Tfh-associated genes have been linked to enhanced CRC survival. In stage II CRC TLS, an escalation in the number of FoxP3⁺ T regulatory cells (Tregs) is regarded as a negative prognostic factor. Moreover, within TLS, T lymphocytes shield B lymphocytes from the immunosuppressive effects of the TME. B lymphocyte activation is succeeded by class recombination (CSR) and somatic hypermutation (SHM). Dendritic cells (DCs) constitute a vital cellular component of the TLS T compartment. During steady state and early stages of CRC, specialized antigen-presenting cells such as DCs migrate to regional lymph nodes through afferent lymphatics. They deliver MHC antigen-derived peptide complexes (tumor antigens) to naïve CD4⁺ and CD8⁺ T cells, which subsequently infiltrate the tumor site as antigen-specific T cells. Key DC markers studied in TLS include CD83 and DC-LAMP. Research has indicated that the DC-LAMP gene signature in tumor TLS reflects Th1 cell targeting, cytotoxicity, and T cell activation. This review comprehensively outlines the functions performed by distinct cell subsets within tertiary lymphoid structures (TLS) in tumors.