Enhancing radiotherapy response via intratumoral injection of the TLR9 agonist CpG to stimulate CD8 T cells in an autochthonous mouse model of sarcoma.
| العنوان: | Enhancing radiotherapy response via intratumoral injection of the TLR9 agonist CpG to stimulate CD8 T cells in an autochthonous mouse model of sarcoma. |
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| المؤلفون: | Su C; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA., Kent CL; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA., Pierpoint M; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA., Floyd W; MD Anderson Cancer Center, Houston, TX, USA., Luo L; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA., Wiliams NT; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA., Ma Y; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA., Peng B; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA., Lazarides AL; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA., Subramanian A; Department of Radiation Oncology, Stanford University, Stanford, CA, USA., Himes JE; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA., Perez VM; Tempus AI, Inc., Durham, NC, USA., Hernansaiz-Ballesteros RD; Tempus AI, Inc., Durham, NC, USA., Roche KE; Tempus AI, Inc., Durham, NC, USA.; QuantBio, LLC., Durham, NC, USA., Modliszewski JL; QuantBio, LLC., Durham, NC, USA., Selitsky SR; Tempus AI, Inc., Durham, NC, USA.; QuantBio, LLC., Durham, NC, USA., Mari Shinohara; Department of Immunology, Duke University, Durham, NC, USA., Wisdom AJ; Department of Radiation Oncology, Harvard University, Cambridge, MA, USA., Moding EJ; Stanford Cancer Institute, Stanford University, Stanford, CA, USA.; Department of Radiation Oncology, Stanford University, Stanford, CA, USA., Mowery YM; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.; MD Anderson Cancer Center, Houston, TX, USA.; Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA., Kirsch DG; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.; Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Jan 04. Date of Electronic Publication: 2024 Jan 04. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Radiation therapy is frequently used to treat cancers including soft tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to radiation therapy (RT) in transplanted tumors, but the mechanism(s) remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft tissue sarcomas with high tumor mutation burden. Treatment with a single fraction of 20 Gy RT and two doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to RT + CpG, we performed bulk RNA-seq, single-cell RNA-seq, and mass cytometry. Sarcomas treated with 20 Gy and CpG demonstrated increased CD8 T cells expressing markers associated with activation and proliferation, such as Granzyme B, Ki-67, and interferon-γ. CpG + RT also upregulated antigen presentation pathways on myeloid cells. Furthermore, in sarcomas treated with CpG + RT, TCR clonality analysis suggests an increase in clonal T-cell dominance. Collectively, these findings demonstrate that RT + CpG significantly delays tumor growth in a CD8 T cell-dependent manner. These results provide a strong rationale for clinical trials evaluating CpG or other TLR9 agonists with RT in patients with soft tissue sarcoma. Competing Interests: DGK is a co-founder of Xrad Therapeutics, which is developing radiosensitizers, and serves on the Scientific Advisory Board of Lumicell, which is commercializing intraoperative imaging technology. DGK is a co-inventor on patents for radiosensitizers and an intraoperative imaging device. DGK also receives funding for a clinical trial from a Stand Up To Cancer (SU2C) Catalyst Research Grant with support from Merck. The laboratory of DGK received funding from Xrad Therapeutics, Merck, Bristol-Myers Squibb, but this did not support the research described in this manuscript. DGK received funding from Varian Medical Systems and an antibody to OX-40 from Bristol-Myers Squibb, which were used to support experiments in this manuscript. The other authors have declared that no conflict of interest exists. |
| معلومات مُعتمدة: | R38 CA245204 United States CA NCI NIH HHS; F30 CA268910 United States CA NCI NIH HHS; P30 CA014236 United States CA NCI NIH HHS; T32 GM007171 United States GM NIGMS NIH HHS; F30 CA221268 United States CA NCI NIH HHS; R35 CA197616 United States CA NCI NIH HHS |
| تواريخ الأحداث: | Date Created: 20240123 Latest Revision: 20240719 |
| رمز التحديث: | 20240719 |
| مُعرف محوري في PubMed: | PMC10802286 |
| DOI: | 10.1101/2024.01.03.573968 |
| PMID: | 38260522 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 2692-8205 |
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| DOI: | 10.1101/2024.01.03.573968 |