Therapeutic Lymphoid Organogenesis in the Tumor Microenvironment

The inflammatory status of the tumor microenvironment (TME) has been heavily investigated in recent years. Chemokine- and cytokine-signaling pathways such as CCR7, CXCR5, lymphotoxin, and IL-36, which are involved in the generation of secondary lymphoid organs and effector immune responses, are now recognized as having value both as prognostic factors and as immunomodulatory therapeutics in the context of cancer. Furthermore, when produced in the TME, these mediators have been shown to promote the recruitment of immune cells, including T cells, B cells, dendritic cells (DCs), and other specialized immune cell subsets such as follicular DCs and T follicular helper cells, in association with the formation of "tertiary" lymphoid structures (TLSs) within or adjacent to sites of disease. Although TLSs are composed of a heterogeneous collection of immune cell types, whose composition differs based on cancer subtype, the qualitative presence of TLSs has been shown to represent a biomarker of good prognosis for cancer patients. A comprehensive understanding of the role each of these pathways plays within the TME may support the rational design of future immunotherapies to selectively promote/bolster TLS formation and function, leading to improved clinical outcomes across the vast range of solid cancer types.