| المؤلفون: |
Himes JE; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA., Wisdom AJ; Harvard Radiation Oncology Program, Harvard University, Boston, MA, 02115., Wang L; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA., Shepard SJ; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA., Daniel AR; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA., Williams N; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA., Luo L; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA., Ma Y; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA., Mowery YM; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27710, USA.; Duke Cancer Institute, Durham, NC, 27710, USA.; Department of Head and Neck Surgery & Communication Sciences, Duke University Medical Center, Durham, NC, 27710, USA., Kirsch DG; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA.; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27710, USA.; Duke Cancer Institute, Durham, NC, 27710, USA. |
| مستخلص: |
The adaptive immune system plays an essential anti-tumor role through immunosurveillance and response to immunotherapies. Characterizing phenotypic features and mechanisms of dysfunction of tumor-specific T cell populations may uncover novel immunotherapeutic targets and biomarkers of response. To study tumor-specific T cell responses in vivo , a tumor model must express a known neoantigen. While transplant models with known neoantigen expression are widely available, autochthonous tumor models in which the tumor coevolves with the immune system are limited. In this study, we combined CRISPR/Cas9 and sleeping beauty transposase technology to develop an autochthonous orthotopic murine sarcoma model with oncogenic Kras G12D , functionally impaired p53, and expression of known MHCI and MHCII sarcoma neoantigens. Using MHC tetramer flow cytometry, we identified a tumor-specific immune response in the peripheral blood as early as 10 days after tumor induction leading to tumor clearance. Tumors developed at high penetrance after co-depletion of CD8 and CD4 T cells, but depletion of either CD8 or CD4 T cells alone was insufficient to permit tumor growth. These results suggest that CD8 and CD4 T cells can independently contribute to immunosurveillance leading to clearance of sarcomas expressing MHCI and MHCII neoantigens.
Competing Interests: Competing Interests: DGK is a cofounder of and stockholder in XRAD Therapeutics, which is developing radiosensitizers. DGK is a member of the scientific advisory board and owns stock in Lumicell Inc, a company commercializing intraoperative imaging technology. None of these affiliations represents a conflict of interest with respect to the work described in this manuscript. DGK is a coinventor on a patent for a handheld imaging device and is a coinventor on a patent for radiosensitizers. XRAD Therapeutics, Merck, Bristol Myers Squibb, and Varian Medical Systems provide research support to DGK, but only funds from Merck supported the research described in this manuscript. The other authors have no conflicting financial interests. |
