title: TGFβ inhibition prior to hypofractionated radiation enhances efficacy in preclinical models.
abstract: The immune infiltrate in colorectal cancer has been correlated with outcome, such that individuals with higher infiltrations of T cells have increased survival independent of the disease stage. For patients with lower immune infiltrates, overall survival is limited. Because the patients with colorectal cancer studied have received conventional cancer therapies, these data may indicate that the pretreatment tumor environment increases the efficacy of treatments such as chemotherapy, surgery, and radiotherapy. This study was designed to test the hypothesis that an improved immune environment in the tumor at the time of treatment will increase the efficacy of radiotherapy. We demonstrate that inhibition of TGFβ using the orally available small-molecule inhibitor SM16 improved the immune environment of tumors in mice and significantly improved the efficacy of subsequent radiotherapy. This effect was not due to changes in radiosensitivity, epithelial-mesenchymal transition, or changes in vascular function in the tumor; rather, this effect was dependent on adaptive immunity and resulted in long-term protective immunity in cured mice. These data demonstrate that immunotherapy is an option to improve the immune status of patients with poor tumor infiltrates and that pretreatment improves the efficacy of radiotherapy.
authors.affiliation: Department of Radiation Medicine, Oregon Health and Science University, Portland, Oregon.
authors.forename: Kristina H
authors.initials: KH
authors.lastname: Young
authors.affiliation: Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon. The Oregon Clinic, Portland, Oregon.
authors.forename: Pippa
authors.initials: P
authors.lastname: Newell
authors.affiliation: Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cottam
authors.affiliation: Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon.
authors.forename: David
authors.initials: D
authors.lastname: Friedman
authors.affiliation: Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon.
authors.forename: Talicia
authors.initials: T
authors.lastname: Savage
authors.affiliation: Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Baird
authors.affiliation: Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Akporiaye
authors.affiliation: Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gough
authors.affiliation: Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon. The Oregon Clinic, Portland, Oregon. marka.crittenden@providence.org.
authors.forename: Marka
authors.initials: M
authors.lastname: Crittenden
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects / Q000276:immunology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D053961:Azabicyclo Compounds / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000532:radiotherapy; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000532:radiotherapy; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020360:Neoadjuvant Therapy / Q000379:methods; D009368:Neoplasm Transplantation; D011836:Radiation Tolerance / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D053961:Azabicyclo Compounds; C528106:SM16 compound; D016212:Transforming Growth Factor beta