Spatial Profiling Identifies Tumor-Associated Stroma Enrichment and MIF as Potential Immunotherapy Targets in Primary
Christopher Kuo1,2, Krinio Giannikou1, Nuoya Wang3
1Division of Hematology-Oncology, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, California.
Purpose:
The tumor microenvironment (TME) plays a vital role in cancer survival and progression and may play roles in drug resistance and immune escape. To date, few studies have detailed the TME of Ewing sarcoma.
Experimental Design:
We performed spatially resolved transcriptomics of primary treatment-naïve Ewing sarcoma tumor biopsies from patients with or without clinical metastasis, complemented by high-plex spatial proteomic analysis.
Results:
We discovered greater stromal enrichment in localized Ewing sarcoma primary tumors compared with metastasis-associated Ewing sarcoma primary tumors. Through spatial ligand-receptor analysis, we showed that the stroma-enriched regions harbor unique extracellular matrix-related cytokines, immune recruitment, and proinflammatory microenvironmental signals, implying that Ewing sarcoma stroma may play an antitumor role by acting as an immune recruitment center. All Ewing sarcoma tumors expressed protumorigenic macrophage migration inhibitory factor (MIF)-CD74 immune signaling connectivity, suggesting a potential immune-evasive mechanism.
Conclusions:
In addition to the immune recruitment role of tumor-associated stroma, our findings provide spatial insights into the TME of Ewing sarcoma and provide a rationale for the preclinical investigation of MIF as a potential target for Ewing sarcoma immunotherapy.
