title: Cryotherapy with concurrent CpG oligonucleotide treatment controls local tumor recurrence and modulates HER2/neu immunity.
abstract: Percutaneous cryoablation is a minimally invasive procedure for tumor destruction, which can potentially initiate or amplify antitumor immunity through the release of tumor-associated antigens. However, clinically efficacious immunity is lacking and regional recurrences are a limiting factor relative to surgical excision. To understand the mechanism of immune activation by cryoablation, comprehensive analyses of innate immunity and HER2/neu humoral and cellular immunity following cryoablation with or without peritumoral CpG injection were conducted using two HER2/neu(+) tumor systems in wild-type (WT), neu-tolerant, and SCID mice. Cryoablation of neu(+) TUBO tumor in BALB/c mice resulted in systemic immune priming, but not in neu-tolerant BALB NeuT mice. Cryoablation of human HER2(+) D2F2/E2 tumor enabled the functionality of tumor-induced immunity, but secondary tumors were refractory to antitumor immunity if rechallenge occurred during the resolution phase of the cryoablated tumor. A step-wise increase in local recurrence was observed in WT, neu-tolerant, and SCID mice, indicating a role of adaptive immunity in controlling residual tumor foci. Importantly, local recurrences were eliminated or greatly reduced in WT, neu tolerant, and SCID mice when CpG was incorporated in the cryoablation regimen, showing significant local control by innate immunity. For long-term protection, however, adaptive immunity was required because most SCID mice eventually succumbed to local tumor recurrence even with combined cryoablation and CpG treatment. This improved understanding of the mechanisms by which cryoablation affects innate and adaptive immunity will help guide appropriate combination of therapeutic interventions to improve treatment outcomes.
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Veenstra
authors.affiliation: Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Gibson
authors.affiliation: Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Littrup
authors.affiliation: Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Joyce D
authors.initials: JD
authors.lastname: Reyes
authors.affiliation: Karmanos Cancer Institute, Detroit, Michigan. Department of Urologic Oncology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cher
authors.affiliation: Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, Ohio.
authors.forename: Akira
authors.initials: A
authors.lastname: Takashima
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan. Karmanos Cancer Institute, Detroit, Michigan. weiw@karmanos.org.
authors.forename: Wei-Zen
authors.initials: WZ
authors.lastname: Wei
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy; D018899:CpG Islands; D017679:Cryotherapy; D005260:Female; D018734:Genes, erbB-2; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000517:prevention & control*; D009841:Oligonucleotides / Q000494:pharmacology*
chemical_list: D009841:Oligonucleotides
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