{
  "abstract": "Background Metastatic pulmonary osteosarcoma is a devastating disease in desperate need of new therapies. We recently showed that mRNA-lipid particle aggregates (LPAs) can improve survival in a murine metastatic pulmonary osteosarcoma model (K7M2) by reprogramming tumor-microenvironment (TME) and enhancing tumor antigen spread. 1 However, a noticeable group of treated animals succumbed to tumor outgrowth, suggesting the development of tumor resistance.Methods The mRNA-LPA mediated response was studied in BALB/c mice bearing pulmonary K7M2 tumors. Tumors from treated animals, including both non-responders and long-term survivors, were analyzed using transcriptomics profiling and deconvolution analysis. Immuno-fluorescent staining and flowcytometry were employed to characterize the immune cell populations and histologic features.Results Bulk RNA-sequencing data and deconvolution analysis revealed distinct gene signatures in non-responding animals, suggesting an increase of suppressive myeloid cells and shift of activated T cells toward Th2 cells or regulatory T cell (Tregs) phenotypes. On the other hand, the responders exhibited enhanced Th1 cell activation in the IL-1 family signaling pathway. In addition, among a set of anti-inflammatory genes being highly expressed in non-responders, we identified the most significant one, Vsig4, which encodes a strong T cell negative modulator that inhibits T cell proliferation and induces T cell death in vitro. Immuno-fluorescent staining and flowcytometry were performed to confirm expression of VSIG4 on macrophages. Surprisingly and interestingly, the VSIG4-positive cells were arranged along the border of tumor nodule reminiscent of a granuloma walling off infection, implying its potential role of suppressing T cell function, forming immunosuppressive niches and orchestrating tumor invasion in non-responders.Conclusions Our data suggests that suppressive myeloid cells contribute to tumor immune evasion, as a compensatory response to mRNA-LPA treatment that may be antagonized with immune checkpoint inhibition. VSIG4, which is exclusively expressed on macrophages, may be a potent therapeutic target to overcome resistance in metastatic OSA.Acknowledgements We appreciate funding from the NIH 5R01CA266857-03 to Dr. Elias Sayour and V-Foundation for cancer research to Dr. John Ligon.Reference Mendez-Gomez HR, DeVries A, Castillo P, et al. RNA aggregates harness the danger response for potent cancer immunotherapy. Cell. 2024;187(10):2521–2535.e21.Ethics Approval The animal study was approved by the University of Florida Institutional Animal Care and Use Committee, approval number IACUC202300000363.",
  "authors": [
    {
      "affiliations": [
        "University of Florida, Gainesville, FL, USA"
      ],
      "name": "Chong Zhao"
    },
    {
      "affiliations": [
        "University of Florida, Gainesville, FL, USA"
      ],
      "name": "Hector Mendez-Gomez"
    },
    {
      "affiliations": [
        "University of Florida, Gainesville, FL, USA"
      ],
      "name": "Chao Xie"
    },
    {
      "affiliations": [
        "University of Florida, Gainesville, FL, USA"
      ],
      "name": "Frances Weidert"
    },
    {
      "affiliations": [
        "University of Florida, Gainesville, FL, USA"
      ],
      "name": "Dingpeng Zhang"
    },
    {
      "affiliations": [
        "University of Florida, Gainesville, FL, USA"
      ],
      "name": "Darrice Montgomery"
    },
    {
      "affiliations": [
        "University of Florida, Gainesville, FL, USA"
      ],
      "name": "Jonathan Chardon-Robles"
    },
    {
      "affiliations": [
        "University of Florida, Gainesville, FL, USA"
      ],
      "name": "Andria Doty"
    },
    {
      "affiliations": [
        "University of Florida, Gainesville, FL, USA"
      ],
      "name": "John A Ligon"
    },
    {
      "affiliations": [
        "University of Florida, Gainesville, FL, USA"
      ],
      "name": "Elias Sayour"
    }
  ],
  "title": "908 Granulomatous-like resistance to RNA cluster vaccines leads to escape in osteosarcoma",
  "uid": "0819e8b3-df35-5582-ba02-16c817ec32d6"
}