Trends in Immunology
ReviewTertiary lymphoid structures in cancer and beyond
Introduction
That adaptive immune responses against infectious agents, grafted organs and, in some cases, tumors are generated in secondary lymphoid organs (SLO), particularly in the LN draining the pathological sites, has been extensively documented and is broadly accepted. In recent years, however, increasing evidence suggests that specific immune reactions may also be generated outside SLO, directly in the tissues where the infection, the graft, or the tumor is present.
A first set of observations supporting this hypothesis comes from studies of the immune responses in lower vertebrates ontogenically lacking LN [1]. The emergence of LN in mammals and in some bird species dates to ∼200 million years ago. In contrast, lymphoid structures associated with the gut (gut associated lymphoid tissues – GALT) appear much earlier in evolution, being present in cartilaginous fishes, such as sharks, where they appear to play a role in the generation of adaptive immune responses. GALT are induced by external stimuli and exhibit most features associated with ectopic lymphoid structures found in mammals. They may represent the most ancient examples of TLS during the evolution of vertebrates (defining characteristics of TLS are discussed in Box 1). Interestingly, the genesis of TLS and LN is based on the participation of the same set of molecules [i.e., lymphotoxin (LT)-α and LT–β; lymphoid chemokines CCL19, CCL21, and CXCL13; tumor necrosis factor-alpha (TNF-α); and RANK ligand].
A second set of observations in support of the notion that specific immune reactions may also be generated directly in the tissue harboring the insult comes from studies of mice devoid of LN, spleen, and Peyer's patches. Infection of such mice with the influenza virus induces the neogenesis of lung TLS; importantly, these mice are able to generate protective primary and secondary immune responses as efficient as those generated in their wild type counterparts 2, 3. These findings argue that SLO are dispensable for the generation of robust primary and memory immune responses.
A third line of evidence comes from the analysis of human pathologies. TLS are induced in the case of chronic infections, graft rejection, autoimmune inflammatory diseases, and cancers, and correlate with disease evolution, as discussed further below. These varied lines of evidence support the notion that immune responses to specific pathogen or inflammatory challenges may occur in TLS.
In this review, we explore two main questions:
- (i)
What is the impact of TLS at sites of chronic infection and inflammation? Depending on the context, TLS may be associated with resolution or exacerbation of the disease, and we discuss these different possibilities.
- (ii)
What are the roles of TLS in cancer? We examine evidence that associates the presence of TLS with both beneficial and deleterious outcomes in different types of cancers, and discuss how TLS could impact response to therapies. An improved understanding of the role of TLS and the immune response within tumors may help guide treatment decisions and provide insights leading to more effective therapeutic approaches.
Section snippets
TLS and allograft rejection
Chronic alloimmune responses occurring in murine cardiac allografts [4], rat aortic transplants [5], kidney [6], or skin transplants [7] induce TLS neogenesis. TLS presence is associated with chronic rejection [4], and both effector and memory T cell responses capable of perpetuating the rejection process can be generated in these structures [7]. In humans, TLS were detected in chronically rejected kidney and heart grafts 5, 8, and the presence of TLS has been shown to correlate with chronic
Tertiary lymphoid structures in cancer
The tumor microenvironment presents many analogies to settings of chronic inflammation, but exhibits profound immunosuppressive characteristics including infiltration of regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells (reviewed in 34, 35). This specific feature, as compared with other chronic inflammatory contexts, raises the question: can lymphoid neogenesis occur in immunosuppressive microenvironments, such as those found in tumors?
Concluding remarks
TLS are found in tissues in many pathological situations which have in common the presence of an ongoing chronic inflammation. It is still a matter of debate whether they are only witnesses of the inflammatory milieu or whether they are sites where adaptive immune reactions against the local tissue components are generated or reactivated. Although correlative, the observations that TLS high densities correlate with graft rejection, auto-immune disease aggravation or, conversely, with longer
Acknowledgments
We wish to acknowledge the work of Romain Remark, Diane Damotte and Marco Alifano, who generated some of the data depicted in Figure 2 in addition to the work referenced in 62 (Remark, R. et al. (2013) Clin. Cancer Res. 19, 4079-4091). We also wish to acknowledge the participation of other members of the laboratory, clinicians and pathologies who participated in the articles referenced in our review. This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM),
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