Abstract
There is emerging evidence that the adaptive anti-tumor activity may be orchestrated by secondary lymphoid organ-like aggregates residing in the tumor microenvironment. Known as tertiary lymphoid structures, these lymphoid aggregates serve as key outposts for lymphocyte recruitment, priming and activation. They have been linked to favorable outcomes in many tumor types, and more recently, have been shown to be effective predictors of response to immune checkpoint blockade. We have previously described a 12-chemokine (12-CK) transcriptional score which recapitulates an overwhelming enrichment for immune-related and inflammation-related genes in colorectal carcinoma. Subsequently, the 12-CK score was found to prognosticate favorable survival in multiple tumors types including melanoma, breast cancer, and bladder cancer. In the current study, we summarize the discovery and validation of the 12-CK score in various tumor types, its relationship to TLSs found within the tumor microenvironment, and explore its potential role as both a prognostic and predictive marker in the treatment of various cancers.
Highlights
Effective adaptive immune response against cancer requires the rendezvous between the tumor antigen/major histocompatibility complex expressed on mature dendritic cells (DC) traveling from the primary tumor site and the resident CD4+ and CD8+ T cells in the secondary lymphoid organs
B cells are concurrently activated in the secondary lymphoid organs upon antigen binding and receive help from T follicular helper cells (Tfh) to proliferate and form a secondary follicle, which progressively becomes a germinal center that persists until antigenic clearance
There is emerging evidence that adaptive anti-tumor immunity can be orchestrated at secondary lymphoid organ-like aggregates within the tumor microenvironment (TME) called tertiary lymphoid structures (TLS) [3, 4]
Summary
Effective adaptive immune response against cancer requires the rendezvous between the tumor antigen/major histocompatibility complex expressed on mature dendritic cells (DC) traveling from the primary tumor site and the resident CD4+ and CD8+ T cells in the secondary lymphoid organs. TLSs were first described in chronic inflammatory conditions, such as infection, autoimmune disease, and organ transplant rejection [2] They are posited to be 1) the gateway of naïve lymphocyte infiltration into the TME; 2) privileged sites for coordinated tumor antigen presentation and lymphocyte priming, differentiation, and proliferation, leading to a robust tumor-specific immune response. In line with these hypotheses, preclinical work has demonstrated the ability of adoptively transferred naïve CD8+ T cells to directly enter the TME through interactions with TLSassociated high endothelial venules (HEVs) in mice devoid of secondary lymphoid organs [5]. The clinical benefits of TLS within the TME has been recapitulated in the setting of immunotherapy in other tumor types [17]
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