STINGing the Tumor Microenvironment to Promote Therapeutic Tertiary Lymphoid Structure Development

Abstract

Tertiary lymphoid structures (TLS), also known as ectopic lymphoid structures (ELS) or tertiary lymphoid organs (TLO), represent a unique subset of lymphoid tissues noted for their architectural similarity to lymph nodes, but which conditionally form in peripheral tissues in a milieu of sustained inflammation. TLS serve as regional sites for induction and expansion of the host B and T cell repertoires via an operational paradigm involving mature dendritic cells (DC) and specialized endothelial cells (i.e. high endothelial venules; HEV) in a process directed by TLS-associated cytokines and chemokines. Recent clinical correlations have been reported for the presence of TLS within tumor biopsies with overall patient survival and responsiveness to interventional immunotherapy. Hence, therapeutic strategies to conditionally reinforce TLS formation within the tumor microenvironment (TME) via the targeting of DC, vascular endothelial cells (VEC) and local cytokine/chemokine profiles are actively being developed and tested in translational tumor models and early phase clinical trials. In this regard, a subset of agents that promote tumor vascular normalization (VN) have been observed to coordinately support the development of a pro-inflammatory TME, maturation of DC and VEC, local production of TLS-inducing cytokines and chemokines, and therapeutic TLS formation. This mini-review will focus on STING agonists, which were originally developed as anti-angiogenic agents, but which have recently been shown to be effective in promoting VN and TLS formation within the therapeutic TME. Future application of these drugs in combination immunotherapy approaches for greater therapeutic efficacy is further discussed.

Keywords: STING agonists; T cells; dendritic cells; immunotherapy; tertiary lymphoid structures; tumor; vaccine; vascular normalization.

Figure 1

Treatment of tumors with STING agonists induces vascular normalization (VN), increased inflammatory immune cell infiltration and TLS formation. Untreated tumors exhibit dysfunctional blood vessels that limit immune cell entry into the tumor microenvironment (TME) in support of tumor progression (left). Provision of STING agonists (1, right) into the TME leads to the activation of STING⁺ stromal cells (2), including dendritic cells (DC) and vascular endothelial cells (VEC), leading to enhanced endothelial cell expression of adhesion molecules, improved vascular integrity/perfusion, and pro-inflammatory immune cell infiltration. A subset of therapeutically-conditioned VEC may differentiate into PNAd⁺ high endothelial venules (HEV). STING activated DC and HEV produce TLS-promoting cytokines/chemokines CCL19, CCL21, lymphotoxins, CXCL10 and IFNβ, which serve to recruit T cells and DC into the TME in support of non-classic, immature TLS formation proximal to HEV (3). CXCL13, required for optimal B cell recruitment into the TME and for germinal center (GC) formation within TLS, is only poorly produced in the STING agonist-conditioned tumors, precluding formation of classical, mature TLS. Combination protocols will likely be required for conversion of immature TLS into B cell/GC-rich classical, mature TLS (4) and/or to improve the therapeutic benefits associated with treatment-induced TLS formation (5). Image created with BioRender.com.