Abstract B038: Inflammatory spatial niches distinguished by antigen presentation and interferon response programs explain the high immune response rate of desmoplastic melanoma: Comparison of biopsies from SWOG S1512 and S1616

Abstract Background: Immune checkpoint blockade (ICB) has revolutionized cancer treatment by inducing remission in patients who were refractory to traditional therapies. By removing the brakes from anti-tumor immune cells, ICB has led to remarkable responses in several cancer types. However, these responses are not homogenous. Within cutaneous melanomas, desmoplastic melanomas (DMs) present with markedly better responses to ICB; a recent phase II trial (SWOG S1512, NCT02775851) with pembrolizumab (anti-PD1) demonstrated an overall response rate of 89%. These findings contrast with prior work in “cold” tumors, such as pancreatic ductal adenocarcinoma, where prominent desmoplasia has been found to inhibit the anti-tumor immune response. This difference brings us to question the intrinsic (tumor cell) and extrinsic (microenvironment) derived signals that position DM tumor microenvironments (TMEs) to respond this positively to ICB. Methods: We performed spatial transcriptomics on biopsies from patients with DM (n=7 pre and n=14 post -treatment from S1512) and non-desmoplastic melanomas (non-DM, n=15 pre and n=14 post -treatment from S1616) using NanoString CosMx (1,000-plex). We collected 2,661,379 high-quality spatially-resolved single cell transcriptomes with readily identifiable tumor, stroma, and immune cell populations. We performed differential gene expression analysis via pseudo-bulking of in silico isolated cell populations with gene set enrichment analysis. Spatial analyses consisted of the identification of differential neighborhood composition (cell type) and function (expressed genes and pathways) between DM and non-DM TMEs. Results: DM tumor cells and associated stroma, fibroblasts, were found to differentially express potent immune cell attractants such as CCL19 and CCL21, known to recruit T and dendritic cells. In contrast, non-DM tumor cells markedly upregulated Treg associated chemokine, CCL28. Spatial analyses revealed DM tumor cells to not only be physically proximal to fibroblasts, consistent with histopathology, but also to vascular endothelial cells that may facilitate immune cell recruitment into DM tumors. DM TMEs were further distinguished through tumor cell spatial neighborhoods differentially enriched for antigen presentation and interferon response pathways. In line with the inflammatory nature of these neighborhoods in DM TMEs and increased expression of chemokines by DM tumor cells, we also found these niches to be rich with lymphocytes (B and T cells) and myeloid cells that are likely the agents poised to enact the efficacious anti-tumor response observed in patients with DM treated with ICB. Conclusion: In all, through spatially-resolved transcriptomics, we found DM tumors to possess uniquely inflammatory spatial niches that may facilitate a more positive response to ICB through prevalent local vasculature to mediate immune cell infiltration into the TME and coordinated upregulation of antigen presentation machinery in an interferon response associated manner to allow for immune cell recognition and thus cancer clearance. Citation Format: Daniel G. Chen, Amanda Truong, Nataly Naser Al Deen, Cynthia R. Gonzalez, Ignacio Baselga-Carretero, Jia M. Chen, Kari L. Kendra, Zeynep Eroglu, Siwen Hu-Lieskovan, Ari M. Vanderwalde, David A. Wada, Jose A. Plaza, Michael C. Wu, Philip O. Scumpia, Antoni Ribas, Katie M. Campbell. Inflammatory spatial niches distinguished by antigen presentation and interferon response programs explain the high immune response rate of desmoplastic melanoma: Comparison of biopsies from SWOG S1512 and S1616 [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B038.