Abstract
Tertiary lymphoid structures (TLS) are ectopically formed aggregates of organized lymphocytes and antigen-presenting cells that occur in solid tissues as part of a chronic inflammation response. Sharing structural and functional characteristics with conventional secondary lymphoid organs (SLO) including discrete T cell zones, B cell zones, marginal zones with antigen presenting cells, reticular stromal networks, and high endothelial venues (HEV), TLS are prominent centers of antigen presentation and adaptive immune activation within the periphery. TLS share many signaling axes and leukocyte recruitment schemes with SLO regarding their formation and function. In cancer, their presence confers positive prognostic value across a wide spectrum of indications, spurring interest in their artificial induction as either a new form of immunotherapy, or as a means to augment other cell or immunotherapies. Here, we review approaches for inducible (iTLS) that utilize chemokines, inflammatory factors, or cellular analogues vital to TLS formation and that often mirror conventional SLO organogenesis. This review also addresses biomaterials that have been or might be suitable for iTLS, and discusses remaining challenges facing iTLS manufacturing approaches for clinical translation.
Highlights
The presence of infiltrating immune cell populations is a prominent histological feature of most solid tumors that with some exceptions [1, 2], often confers positive prognostic significance across a wide spectrum of indications [3]
This is best exemplified in hepatocellular carcinoma (HCC) [35], and suggests that while Tertiary lymphoid structures (TLS) represent an integral part of the anti-tumor immune response, their function is likely influenced by a number of contextual signals, including those afforded by local stroma, secreted inflammatory factors, other resident immune populations, local vasculature, and epithelium [36]
This review provides an overview of what strategies have been and might be employed to artificially induce TLS, how inducible TLS (iTLS) may be employed as a novel therapeutic, and what technical difficulties must be addressed prior to manufacturing iTLS at a clinical level
Summary
The presence of infiltrating immune cell populations is a prominent histological feature of most solid tumors that with some exceptions [1, 2], often confers positive prognostic significance across a wide spectrum of indications [3]. There are reports in which TLS are associated with negative prognostication or disease progression This is best exemplified in hepatocellular carcinoma (HCC) [35], and suggests that while TLS represent an integral part of the anti-tumor immune response, their function is likely influenced by a number of contextual signals, including those afforded by local stroma, secreted inflammatory factors, other resident immune populations, local vasculature, and epithelium [36]. In addition to TLS-associated chemokines, LTBR signaling regulates the expression of a number of homeostatic cytokines and growth factors important to SLO organogenesis and to TLS formation, including IL-7, IL15, and B cell activating factor (BAFF) [44, 72].
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