Tertiary Lymphoid Organs in Cancer Tissues

Abstract

Tertiary lymphoid organs (TLOs) are induced postnatally in non-lymphoid tissues such as those affected by chronic infections, autoimmune diseases, and chronic allograft rejection, and also in cancer tissues. TLOs are thought to provide important lymphocytic functional environments for both cellular and humoral immunity, similar to lymph nodes or Peyer's patches. TLOs have a structure similar to that of lymph nodes or Peyer's patches, including T cell zones, B cell follicles, and high endothelial venules (HEV) without encapsulation. Here, we review recent advances in our knowledge of TLOs in human solid cancers, including their location, structure, methods of evaluation, and clinicopathological impact. We also discuss the formation and/or maintenance of TLOs in cancer tissues in association with the tumor immune microenvironment, cancer invasion, and the tissue structure of the cancer stroma.

Keywords: cancer; tertiary lymphoid organs; tissue structure; tumor immunology; tumor microenvironment.

Figure 1

Histological features of TLOs (45) in chronic pancreatitis (A), IgG4-related lymphoplasmacytic sclerosing pancreatitis (autoimmune pancreatitis) (B,C), and pancreatic ductal adenocarcinoma (PDAC) (D,E). TLOs are distributed evenly in inflamed tissues (A,B) and sometimes concentrated near the target structure (around ducts) (C). In contrast, cancer tissue is surrounded by peritumoral TLOs (D) and a rare pancreatic cancer case has intratumoral TLOs (D). Common PDAC has a paucity of vessels and lacks intratumoral TLOs, although limited cases do have intratumoral TLOs that are richer in tumor-infiltrating lymphocytes and retain relatively intact vascular networks consisting of arterioles, venules, and capillaries without cancer invasion.

Figure 2

Immunohistochemistry detecting a TLO having B-cell follicles, T-cell zones, and HEVs detected by immune-labeling for CD20⁺ cells, CD3⁺ cells, and PNAd⁺ vessels, respectively (45).

Figure 3

Hypothesis of TLO formation/maintenance in cancer tissue, which likely involves (1) the state of antitumor immunity (tumor immunogenicity and host immune reaction) and (2) cancer invasiveness especially to vessels and tissue destruction that significantly affects the state of tissue structures necessary for formation/maintenance of TLOs. TLOs develop in the locations of venules in association with arterioles, venules, and nerve fibers (45). Cancer tissue that has become remodeled, showing absence of functional vascular networks replaced by abnormal blood vessels after invasion of cancer cells (center and left). Peritumoral TLOs can be induced if appropriate immune stimuli are present. Cancer tissue with intratumoral TLOs (right) shows a lower degree of cancer invasiveness, especially to vessels, and an active associated immune reaction. It retains relatively intact vascular networks, transporting immune cells, or other molecules into the cancer tissues, thereby rendering the antitumor immune reaction more effective. The scheme can apply to various solid cancers, although tendency of TLO development may be modified by tissue- and tumor type-specific properties.