Comparative analysis of the immune landscape between wound healing and cancer elucidates dialogue between tumor-initiating stem cells and myeloid populations 2648

Abstract Description Cancer has been viewed as a wound that never heals, in part due to similar myeloid cell populations dominating the inflammatory responses in cancer and wound healing processes. Inflammation in wound healing efficiently resolves, yet in cancer remains chronic and unresolvable. The molecular mechanisms driving key differences between wound healing and cancer is elusive. Our study aims to elucidate the molecular mechanisms which will be critical for developing therapeutic strategies to normalize the inflammatory tumor microenvironment and control malignancy. To achieve this goal, we performed single-cell RNA-sequencing to compare molecular changes induced in myeloid cell populations’ during skin wound healing and skin squamous cell carcinoma progression. We have found that myeloid cell-mediated inflammatory responses in wound healing and cancer progression shared similar cellular compositions, yet the gene signatures of both neutrophils and macrophages remained distinct. Crucially, we have identified a surprising role of tumor-initiating stem cells in shaping the distinct molecular features of macrophages and neutrophils in cancers. In cancer, stem cells orchestrate interactions between neutrophils and macrophages via Csf3 production. Our findings center tumor-initiating stem cells in the tumor microenvironment and highlight specific molecular changes that are responsible for inducing chronic and unresolvable inflammation in the tumors. Funding Sources Supported by NIH R01CA285786 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)