Cancer-Associated Tertiary Lymphoid Structures, from Basic Knowledge Toward Therapeutic Target in Clinic

The tumor growth is under the control of the immune system, and this represents a significant challenge for the development of new therapeutic strategies. It is now recognized that not only the density, but also the organization of tumor-infiltrating immune cells is critical for the shaping of the tumor microenvironment. In human cancers, several levels of structuration of lymphoid aggregates have been observed, including Tertiary Lymphoid Structures (TLS) displaying strong similarities with secondary lymphoid organs. In this review, we discuss about the role of immune cells homing selectively in the T-cell or B-cell zone of TLS with putative consequences on the initiation of efficient cellular and humoral immune responses against tumor, and ultimately on the clinical outcome of cancer patients. However, immunoregulatory cells may also infiltrate TLS and it is thus crucial to determine the circumstances in which TLS might be a site for the development of a suppressive and detrimental immune responses. We also discuss how TLS could be a useful marker of efficient immunotherapy, and raise the question of the capacity of immune-based vaccinations along with immune checkpoint blockade to induce TLS neogenesis. As TLS may represent the best place to induce or amplify protective immunity targeting neoantigens, TLS may be a promising target in order to boost anti-tumoral immunity in cancer patients.