Enhancing radiotherapy response via intratumoral injection of a TLR9 agonist in autochthonous murine sarcomas.

Autor:	Su C; Department of Pharmacology and Cancer Biology and.; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA., Kent CL; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA., Pierpoint M; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA., Floyd W; Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas, USA., Luo L; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA., Williams NT; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA., Ma Y; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA., Peng B; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA., Lazarides AL; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA., Subramanian A; Department of Radiation Oncology, Stanford University, Stanford, California, USA., Himes JE; Department of Pharmacology and Cancer Biology and.; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA., Perez VM; Tempus AI Inc., Durham, North Carolina, USA., Hernansaiz-Ballesteros RD; Tempus AI Inc., Durham, North Carolina, USA., Roche KE; Tempus AI Inc., Durham, North Carolina, USA.; QuantBio LLC, Durham, North Carolina, USA., Modliszewski JL; QuantBio LLC, Durham, North Carolina, USA.; Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA., Selitsky SR; Tempus AI Inc., Durham, North Carolina, USA.; QuantBio LLC, Durham, North Carolina, USA., Shinohara ML; Department of Integrative Immunology.; Department of Molecular Genetics and Microbiology, and.; Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina, USA., Wisdom AJ; Harvard Radiation Oncology Program, Boston, Massachusetts, USA., Moding EJ; Department of Radiation Oncology, Stanford University, Stanford, California, USA.; Stanford Cancer Institute, Stanford University, Stanford, California, USA., Mowery YM; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA.; Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Kirsch DG; Department of Pharmacology and Cancer Biology and.; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA.; Department of Radiation Oncology and.; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2024 Jun 13; Vol. 9 (14). Date of Electronic Publication: 2024 Jun 13.
DOI:	10.1172/jci.insight.178767
Abstrakt:	Radiation therapy (RT) 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 RT in transplanted tumors, but the mechanisms of this enhancement 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 2 doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to CpG+RT, 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 IFN-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 CpG+RT 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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu