Immune and non-immune cell fencing of tumor cells is a widespread and functionally relevant spatial pattern in solid cancers.

Solid tumors are characterized by a spatially heterogeneous mixture of cancer cells, immune cells and other non-tumor cells. Recent characterization of the heterogeneity at the single cell level has revealed spatial patterns of different cell types often lacking a simple geometric structure associated with cancer progression. Here we investigated the occurrence of physical "fencing" of tumor cells by specific immune and non-immune phenotypes in the tumor microenvironment (TME) and the association of these clusters to cancer progression in a wide range of solid tumors formed in different organs. We analyzed published datasets providing patient tumor progression data coupled with imaging mass cytometry (IMC) data obtained from tumor tissues to characterize the presence of fencing clusters of various cell types and their association with differing patient outcomes. The six datasets spanned patients with triple-negative breast cancer (279 patients), lung cancer (416 patients), melanoma (30 patients), colorectal cancer (9 patients), glioma (185 patients), and head and neck cancer (139 patients). Devising and employing simple mechanistic and stochastic spatially-resolved computational models we examine two potential mechanistic hypotheses regarding the pro- and anti-tumor roles of a fencing cluster via physical blocking and chemokine gradient in the local environment, respectively. The fencing structures formed by non-tumor cells in the TME can be important for connecting microscopic cellular patterns to tumor progression and treatment responsiveness to immunotherapy in solid cancers.