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.