Extensive work has focused on tumor epithelial-centric resistance mechanisms to targeted Hedgehog (HH) therapy that include induction of, and selection for, discrete tumor epithelial populations that mediate relapse 7, 8, 9, 10, 11, 12, 13. Skin basal cell carcinomas (BCCs) are ideal for studying the interplay between targeted therapies and epithelial heterogeneity and plasticity because of the high incidence and the ability to serially biopsy from the exact location along a treatment course 7. A better understanding of the immunoregulatory concepts that explain the origin, assembly, and dynamics of the heterogeneous tumor epithelium immune microenvironment is needed. Alongside these efforts, single-cell genomic technologies have revealed that resistance to ICB includes extensive tumor heterogeneity and plasticity, with drug interventions inducing tumor evolution programs that circumvent therapy 5, 6. Newer strategies aimed at improving ICB efficacy with additional blocking antibodies to components of the tumor microenvironment (TME) that enhance antigen presentation to T cells have had only incremental success 2, 3, 4. While the advent of immune checkpoint blockade (ICB) therapies has revolutionized approaches to cancer treatment, the efficacy of these treatments remains inconsistent 1, 2. This work provides mechanistic insights into direct tumor-immune niche dynamics independent of immunosuppression, providing the basis for potential combination tumor therapies. The tumor rapidly drives SCAM differentiation, with intratumoral injections sufficient to instruct naive bone marrow-derived monocytes to polarize within days. Furthermore, SCAMs actively proliferate and self-propagate through multiple serial tumor passages, indicating long-term potential. SCAMs represent a unique tumor-specific TREM2 + population defined by VCAM1 surface expression that is not found in normal homeostatic skin or during wound healing. Within the highly proliferative neighborhood, we find that TREM2 + skin cancer-associated macrophages (SCAMs) support the proliferation of a distinct tumor epithelial population through an immunosuppression-independent manner via oncostatin-M/JAK-STAT3 signaling. Here, we use single-cell and imaging-based spatial analysis to elucidate three microenvironmental neighborhoods surrounding the heterogeneous basal cell carcinoma tumor epithelia. Cancer immunotherapies have revolutionized treatment but have shown limited success as single-agent therapies highlighting the need to understand the origin, assembly, and dynamics of heterogeneous tumor immune niches.
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