D. Delitto

Jul 2026

Abstract PR004: A comprehensive pan-sarcoma single-cell transcriptomic meta-analysis reveals shared molecular programs across subtypes

Sarcomas are rare malignancies that encompass diverse histologic subtypes, despite their shared mesenchymal origins. Given their rarity, completing large-scale studies that aim to elucidate sarcoma biology and derive meaningful therapeutic advancements remains challenging. Identifying shared and distinct molecular programs across sarcomas presents a unique opportunity to efficiently repurpose and advance the therapeutic management of these rare tumors. The purpose of this study was to define the transcriptomic landscape of all human sarcomas. To do this, we performed a systematic meta-analysis of all publicly available single cell RNA sequencing (scRNA-seq) datasets of all human sarcomas. Raw datasets were methodically compiled from the Gene Expression Omnibus (GEO) database. After applying standard quality control metrics, the scanpy pipeline was applied and all datasets were integrated with scVI. Cell types were annotated using a combination of canonical markers and by inferring copy number variation using infer CNV. We screened 1,267 scRNA-seq datasets from 991 studies and identified 210 samples from 34 datasets that met all inclusion and exclusion criteria. After quality control, these datasets encompassed 15 different types of sarcomas, comprised of over a million cells. Following integration and annotation, these tumors were found to have heterogenous tumor microenvironments comprised of several cell types, including tumor, immune, endothelial, and fibroblast lineages, with varying compositions across sarcoma subtypes. CNV inference further distinguished tumor cells from normal cell populations. Among the tumor cells, there were several transcriptional programs shared across sarcomas, including processes related to migration and invasion (PARD3+/AUTS2+/AGAP1+ cells), high translational activity (NPM1+/B2M+/RPL24+ cells), and mesenchyme-like phenotype with matrix remodeling features (THBS2+/COL1A1+/COL6A3+ cells). In summary, we present a comprehensive meta-analysis of all human sarcoma single-cell transcriptomic datasets ever published. To our knowledge, this represents the largest integrated analysis of human sarcomas performed to date. Future analyses will include correlation of transcriptomic signatures with patient outcomes using bulk RNA sequencing data through The Cancer Genome Atlas, along with deriving targeted drug predictions using the drug2cell pipeline. This study establishes a foundational resource for identifying conserved transcriptional programs across sarcomas, with implications for future mechanistic studies and therapeutic repurposing for these rare cancers. Maria Korah, James Agolia, Renceh AB. Flojo, Biren Reddy, Kaylin Yip, Deshka Foster, Michael Longaker, Daniel Delitto. A comprehensive pan-sarcoma single-cell transcriptomic meta-analysis reveals shared molecular programs across subtypes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr PR004.

Maria Korah, J. Agolia, R. Flojo et al. · Cancer Research · 0 citations

Open access Jul 2026

AXL tyrosine kinase inhibition restores anti-PD-1 efficacy in melanoma through tumor-associated macrophage—dependent mechanisms 2255689

Immune checkpoint blockade (ICB) has transformed melanoma care, yet resistance is common and often driven by tumor-associated macrophages (TAMs). AXL, a Gas6-activated tyrosine kinase, is classically a tumor-intrinsic driver of invasion but is predominantly expressed by TAMs in melanoma, suggesting a role in regulating the tumor-immune microenvironment. We tested if AXL inhibition could reprogram macrophage function, disrupt PD-1:PD-L1 interactions, and restore responsiveness to PD-1 blockade. AXL expression was analyzed using TCGA, serum ELISA, and single-cell RNA-seq datasets. ICB-resistant melanoma models (Yumm1.7, B16F10) were treated with warfarin or bemcentinib (AXL inhibitors) alone or with anti-PD-1, with or without macrophage depletion. PD-1:PD-L1 interactions were quantified by immune Förster resonance energy transfer (iFRET). In vitro, polarized macrophages were analyzed for AXL-dependent efferocytosis, T cell crosstalk, and cytokine secretion. AXL was enriched in TAMs across cohorts, with soluble AXL highest in stage IV disease. AXL inhibition reduced tumor burden and synergized with anti-PD-1, efficacy was lost after CSF1R depletion and enhanced by F4/80 depletion. iFRET showed restoration of PD-1:PD-L1 blockade despite unchanged PD-L1 expression. In vitro, AXL function was context-dependent: M1-like macrophages upregulated AXL with immunostimulatory outputs, while M2-like macrophages became more AXL-driven under anti-PD-1. Combination therapy reprogrammed the secretome toward a Th1/Th17, chemokine-rich milieu ↑CXCL9/10, IL-12, IL-23; ↓IL-10, MCP-1). AXL is a dominant TAM-driven regulator of ICB resistance in melanoma. AXL inhibition restores functional PD-1:PD-L1 blockade and rebalances macrophage signaling toward immunostimulation in a microenvironment-specific manner. These findings support AXL as both a biomarker and therapeutic target to overcome ICB resistance, with implications for tailoring macrophage-targeted strategies in refractory melanoma. N/A Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Amanda R. Kirane, David Lee, Saurabh Sharma et al. · Journal of Immunology · 0 citations