Increased representation of CD8 T-lymphocytes in tumors, spontaneously, or after vaccination or adoptive therapy, is essential for immune mediated control of human cancers. T-cell infiltrates are a positive prognostic indicator of patient survival, and it has become clear that the patients who respond clinically to new generation immunotherapies are those in which an immunological infiltrate is already evident prior to treatment. Thus, limited representation of intratumoral T-cells is a major barrier to tumor control, distinct from the barrier created by immunosuppression. Understanding and overcoming this limitation will enable us to extend the effectiveness of many immunotherapies to a broader cross-section of cancer patients.
T cell infiltration into lymphoid and non-lymphoid tissues is controlled by homing receptors (HR) that engage corresponding ligands expressed on tissue-associated vasculature. Naïve T-cells enter LN based on expression of L-selectin and CCR7. These HR bind to peripheral node addressin (PNAd) and the chemokines CCL19/CCL21, respectively, which are expressed on specialized lymph node blood vessels called high endothelial venules (HEV). During differentiation, effector T-cells acquire the ability enter peripheral tissues, including tumors, by upregulating other selectins, integrins and chemokine receptors that bind to ligands expressed on inflamed vasculature. However, we lack a full understanding of which HR expressed by CD8 T-cell effectors control their migration into tumors, how this is influenced by expression of the corresponding ligands on tumor vasculature, and whether ligand expression changes as a result of vessel normalization. We have explored the hypothesis that CD8 T-cell effectors activated in different secondary lymphoid organs express distinct HR, which in turn control infiltration into tumors in different anatomical locations. We identified 3 major populations of primary CD8 T-cell effectors based on site of activation and HR expression pattern, and have established which HR enable infiltration of one of these populations into tumors.
While it has been assumed that all tumor-infiltrating lymphocytes are effectors that differentiate in tumor-draining LN and subsequently enter the tumor, we have shown that naïve CD8 T-cells also can directly enter tumors. These naïve cells differentiate into functional effectors in the tumor, and can promote its control. Naïve CD8 T-cell infiltration depends on L-selectin and CCR7, as in lymph nodes, and on the development of blood vessels in the tumor that express PNAd and CCL21 and resemble lymph node HEV. Similar lymph node-like vasculature has been reported in human tumors along with ectopic organized lymphoid tissue (tertiary lymphoid organs or TLO), and correlated with longer metastasis-free, disease-free, and overall survival.
Development of this vasculature in murine tumors was controlled by a novel mechanism involving effector CD8 T-cells and NK cells that secreted Lymphotoxin-α3 and IFNγ;. This suggests that early infiltration of effectors induces LN-like vasculature, which in turn supports a self-sustaining recruitment of naïve T-cells that differentiate within the tumor. In intraperitoneal but not subcutaneous tumors, this lymph node-like vasculature was also associated with organized aggregates of B-lymphocytes and gp38+ fibroblasts that resembled TLO. The differential expression of these elements in SC and IP tumors reflects differences in immunological tumor microenvironments that remain to be explored further. Nonetheless, these results establish LN-like vasculature as both a consequence of and key contributor to anti-tumor immunity based on its role in promoting T-cell infiltration.
Citation Format: Victor H. Engelhard, David Peske, Amber Woods, Nithya Srinivasan, Colin Brinkman, Andrew Ferguson. T cell trafficking in lymphoid and non-lymphoid tissues. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA23.
- ©2015 American Association for Cancer Research.