Turning Tertiary Lymphoid Structures (TLS) into Hot Spots: Values of TLS in Gastrointestinal Tumors

SIMPLE SUMMARY: Despite considerable improvements in immunotherapy of cancers, how to predict and enhance the anti-tumor immune response remains unknown. As a new emerging player identified in tumor immunology, tertiary lymphoid structure (TLS) has been shown to play critical roles in local tumor immune microenvironments. TLS serves as a guardian located nearest to tumors by providing an arena for lymphocyte maturation and anti-tumor immune responses. Accumulating evidence has shown numerous aspects of TLS, which not only includes its cellular composition and formation process, but also includes how it exerts local anti-tumor immune responses. Our review summarizes recent findings in the characteristics of TLS in gastrointestinal tumors and also gives a brief introduction on how to manipulate TLS formation and anti-tumor immune responses to benefit tumor treatment in the future. ABSTRACT: Tertiary lymphoid structures (TLSs) are ectopic lymphocyte aggregation structures found in the tumor microenvironment (TME). Emerging evidence shows that TLSs are significantly correlated with the progression of gastrointestinal tumors, patients’ prognosis, and the efficacy of adjuvant therapy. Besides, there are still some immunosuppressive factors in the TLSs that may affect the anti-tumor responses of TLSs, including negative regulators of anti-tumor immune responses, the immune checkpoint molecules, and inappropriate tumor metabolism. Therefore, a more comprehensive understanding of TLSs’ responses in gastrointestinal tumors is essential to fully understand how TLSs can fully exert their anti-tumor responses. In addition, targeting TLSs with immune checkpoint inhibitors and vaccines to establish mature TLSs is currently being developed to reprogram the TME, further benefiting cancer immunotherapies. This review summarizes recent findings on the formation of TLSs, the mechanisms of their anti-tumor immune responses, and the association between therapeutic strategies and TLSs, providing a novel perspective on tumor-associated TLSs in gastrointestinal tumors.