Abstract 4290: Visualizing immune surveillance in lung metastasis progression

Abstract As stipulated by the Paget and Fuchs’ “seed and soil” analogy, the establishment of metastases depends on the microenvironment of target tissue; as such, it also depends on the tissue immunosurveillance system. Anti-tumor immune responses are subdued in advanced tumors by various immune suppressory mechanisms, such as by tumor associated CD4 FoxP3 regulatory T-reg cells. But how immune suppression sets in at the sites of metastasis, and how it could be overcome there remains unclear. Using multiphoton and confocal microscopy, we have visualized the immune cell's dynamics that is triggered by various metastatic cancers in the lungs. We found that single, blood-carried cancer cells that settle in the capillary bed triggered strikingly rapid recruitment of CD11c dendritic cells (DCs), which were heterogeneous. Some of those DCs wrapped around the singular cancer cells while other probed their intracellular content by acquiring tumor-derived vesicles. These phagocytic DCs then carried away their cargo towards the draining lymph nodes, thereby initiating tumor antigen cross-presentation. After 24-48 hours, micrometastases became surrounded by T cells that were highly enriched in T-reg. The motility patterns and cell depletion experiments showed that T-reg largely ignored tumor cells but were attracted by the phagocytic tumor-associated DCs. In result of these interactions, the phagocytic DCs became the foci of highly dynamic three-cell interactions between T-reg and the effector T cells, sequestering most T cells at the tumor margin. In this context, we tested the impact of immunomodulatory therapies. The immune cell dynamics that we uncovered in metastases was responsive to therapeutic immune modulation aimed at the tumor-associated phagocytic DCs and also at Programmed Death (PD-1) pathways. Taken together, our intravital dynamic imaging results highlight the duality of metastasis-associated phagocytic DCs. On the one hand, these cells provide tumor antigen cross-presentation and recruit T cells to nascent secondary tumors, but on the other hand, they aid metastasis progression by promoting early on the contact of tumor-infiltrating T cells with T-reg. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4290. doi:1538-7445.AM2012-4290