Perivascular macrophages orchestrate the expansion of pericyte-like mesenchymal cells to create a proangiogenic niche in cancer.

Improving the efficacy of immune checkpoint therapies will require a better understanding of how immune cells are recruited and sustained in tumors. Here, we used the photoconversion of the tumor immune cell compartment to identify newly entering lymphocytes, determine how they change over time, and investigate their egress from the tumor. Combining single-cell transcriptomics and flow cytometry, we found that while a diverse mix of CD8 T cell subsets enter the tumor, all CD8 T cells retained within this environment for more than 72 h developed an exhausted phenotype, revealing the rapid establishment of this program. Rather than forming tumor-resident populations, non-effector subsets, which express TCF-1 and include memory and stem-like cells, were continuously recruited into the tumor, but this recruitment was balanced by concurrent egress to the tumor-draining lymph node. Thus, the TCF-1+ CD8 T cell niche in tumors is highly dynamic, with the circulation of cells between the tumor and peripheral lymphoid tissue to bridge systemic and intratumoral responses.

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Tumor associated macrophages (TAMs) are a highly plastic stromal cell type which are exquisitely polarized by the tumor microenvironment to support cancer progression. Single-cell RNA-sequencing (scRNA-seq) of TAMs from a spontaneous murine model of mammary adenocarcinoma (MMTV-PyMT) identified three distinct polarization trajectories for these cells within the tumor microenvironment. We reveal sub-divisions within the protumoral TAM population with one subset expressing Lyve-1 and residing in a spatial niche proximal to blood vasculature within the tumor. We demonstrate that selective depletion of the Lyve-1+ TAM population significantly slows tumor growth because of a non-redundant role of these cells in orchestrating the platelet derived growth factor-CC (PDGF-CC)-dependent expansion of tumor-resident pericytes which underpins vasculature growth and development. This study uncovers that local pericyte expansion in cancer is not an autonomous event but tightly regulated by the perivascular Lyve-1+ TAM population, which ultimately govern the success of angiogenesis in cancer.

A subset of tumor associated macrophages (TAMs) identified by their expression of the lymphatic vessel endothelial hyaluronan receptor-1 (Lyve-1) reside proximal to blood vasculature and contribute to disease progression. Using a spontaneous murine model of mammary adenocarcinoma (MMTV-PyMT), we show that Lyve-1+ TAMs, which co-express heme oxygenase-1, form coordinated multi-cellular 'nest' structures in the perivascular niche. We show that TAM nest formation is dependent on IL-6 and a communication axis involving CCR5 and its cognate ligands CCL3/4. We demonstrate that Lyve-1+ TAM nests are associated with CD8+ T-cell exclusion from the tumor and the resistance to immune-stimulating chemotherapeutics. This study highlights an unappreciated collaboration between TAMs and uncovers a spatially driven therapeutic resistance mechanism of these cells in cancer which can be therapeutically targeted.

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The clinical success of immune checkpoint blockade (ICB) in some patients has transformed treatment approaches in cancer and offers the hope of durable curative responses. Building from studies of chronic infection, the composition of tumour infiltrating lymphocytes (TILs) and in particular, the spectrum of exhausted CD8 T cells has now been characterised in detail, profiling the phenotype, function, transcriptional regulation and even the epigenetic changes. However, what remains less clear is how intratumoural immune cells interface with populations in the periphery, both in terms of sustaining the response in the cancer, but also in establishing systemic memory responses that can provide long term protection. Here we will succinctly review current understanding of the anti-tumour response, consider the tissue microenvironments that support key cellular subsets and the extent to which cellular migration between these sites impacts the response.