Folkert, I. W. | bioRxiv Science

bioRxiv2022

Mapping and modeling human colorectal carcinoma interactions with the tumor microenvironment

The initiation and progression of cancer are inextricably linked to the tumor microenvironment (TME). Understanding the function of specific cancer-TME interactions poses a major challenge due in part to the complexity of the in vivo microenvironment. Here we predict cancer-TME interactions from single cell transcriptomic maps of both human colorectal cancers (CRCs) and mouse CRC models, ask how these interactions are altered in established, long-term human tumor organoid (tumoroid) cultures, and functionally recapitulate human myeloid-carcinoma interactions in vitro. Tumoroid cultures suppress gene expression programs involved in promoting inflammation and immune cell migration through receptor-ligand interactions, providing a reductive platform for re-establishing carcinoma-immune cell interactions in vitro. Introduction of human monocyte-derived macrophages into tumoroid cultures instructs macrophages to acquire pro-tumorigenic gene expression programs similar to those observed in vivo. This includes hallmark induction of SPP1, encoding Osteopontin, an extracellular CD44 ligand with established oncogenic effects. Taken together, these findings offer a framework for understanding CRC-TME interactions and provide a reductionist tool for modeling specific aspects of these interactions.

cancer biology↗

bioRxiv2022

Single-cell transcriptomics reveal distinct subsets of activated dendritic cells in the tumor microenvironment

Dendritic cells (DCs) are rare in tumors where their heterogeneity remains unclear. To overcome the limitations of surface marker-based analyses, we utilized DC-reporter mice (Zbtb46GFP/+) to isolate tissue and tumor DCs and performed single-cell RNA sequencing (scRNA-seq). The known DC subsets were conserved across tissues, albeit at different frequencies. Activated and mature DCs formed a distinct cluster in both healthy and tumor tissues and displayed the hallmark DC migratory program (migratory DCs). We also identified a distinct subset of activated DCs in tumors that did not induce the migratory program, instead displaying signatures of interferon exposure (interferon-DCs or IFN-DCs). IFN-DCs were proficient in antigen-presentation, supported T cell proliferation, and expressed high levels of T cell-attracting chemokines. IFN-DCs further comprised of IFN1- and IFN2-DCs that were generated from CD11b+ DCs in response to type I or type II interferons respectively. We also identified IFN-DCs in scRNA-seq of human tumor-infiltrating leukocytes. These findings illustrate DC heterogeneity in tumors and suggest the existence of an interferon regulated division of labor among activated DCs whereby the migratory DCs drive T cell priming in draining lymph nodes while the sessile IFN-DCs help recruit T cells and regulate their function in the tumor microenvironment. One Sentence SummaryTumors harbor an interferon-regulated activated sessile subset of dendritic cells.

immunology↗