title: Priming is key to effective incorporation of image-guided thermal ablation into immunotherapy protocols.
abstract: Focal therapies play an important role in the treatment of cancers where palliation is desired, local control is needed, or surgical resection is not feasible. Pairing immunotherapy with such focal treatments is particularly attractive; however, there is emerging evidence that focal therapy can have a positive or negative impact on the efficacy of immunotherapy. Thermal ablation is an appealing modality to pair with such protocols, as tumors can be rapidly debulked (cell death occurring within minutes to hours), tumor antigens can be released locally, and treatment can be conducted and repeated without the concerns of radiation-based therapies. In a syngeneic model of epithelial cancer, we found that 7 days of immunotherapy (TLR9 agonist and checkpoint blockade), prior to thermal ablation, reduced macrophages and myeloid-derived suppressor cells and enhanced IFN-γ-producing CD8+T cells, the M1 macrophage fraction, and PD-L1 expression on CD45+cells. Continued treatment with immunotherapy alone or with immunotherapy combined with ablation (primed ablation) then resulted in a complete response in 80% of treated mice at day 90, and primed ablation expanded CD8+T cells as compared with all control groups. When the tumor burden was increased by implantation of 3 orthotopic tumors, successive primed ablation of 2 discrete lesions resulted in survival of 60% of treated mice as compared with 25% of mice treated with immunotherapy alone. Alternatively, when immunotherapy was begun immediately after thermal ablation, the abscopal effect was diminished and none of the mice within the cohort exhibited a complete response. In summary, we found that immunotherapy begun before ablation can be curative and can enhance efficacy in the presence of a high tumor burden. Two mechanisms have potential to impact the efficacy of immunotherapy when begun immediately after thermal ablation: mechanical changes in the tumor microenvironment and inflammatory-mediated changes in immune phenotype.
authors.affiliation: Department of Biomedical Engineering.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Silvestrini
authors.affiliation: Department of Biomedical Engineering.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Ingham
authors.affiliation: Department of Biomedical Engineering.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Mahakian
authors.affiliation: Department of Biomedical Engineering.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Kheirolomoom
authors.affiliation: Department of Biomedical Engineering.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering.
authors.forename: Brett Z
authors.initials: BZ
authors.lastname: Fite
authors.affiliation: Department of Biomedical Engineering.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Tam
authors.affiliation: Department of Biomedical Engineering.
authors.forename: Samantha T
authors.initials: ST
authors.lastname: Tucci
authors.affiliation: Department of Biomedical Engineering.
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Watson
authors.affiliation: Department of Biomedical Engineering.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Wong
authors.affiliation: Department of Radiation Oncology.
authors.forename: Arta M
authors.initials: AM
authors.lastname: Monjazeb
authors.affiliation: Center for Comparative Medicine.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Hubbard
authors.affiliation: Department of Dermatology, Institute for Regenerative Cures, University of California, Davis, California, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
authors.affiliation: Center for Comparative Medicine.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Borowsky
authors.affiliation: Department of Biomedical Engineering.
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Ferrara
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D002985:Clinical Protocols; D003131:Combined Modality Therapy; D007167:Immunotherapy / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology; D059016:Tumor Microenvironment
chemical_list: C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor