title: Adoptive immunotherapy combined with intratumoral TLR agonist delivery eradicates established melanoma in mice.
abstract: Toll-like receptor (TLR) agonists can trigger broad inflammatory responses that elicit rapid innate immunity and promote the activities of lymphocytes, which can potentially enhance adoptive immunotherapy in the tumor-bearing setting. In the present study, we found that Polyinosinic:Polycytidylic Acid [Poly(I:C)] and CpG oligodeoxynucleotide 1826 [CpG], agonists for TLR 3 and 9, respectively, potently activated adoptively transferred T cells against a murine model of established melanoma. Intratumoral injection of Poly(I:C) and CpG, combined with systemic transfer of activated pmel-1 T cells, specific for gp100(25-33), led to enhanced survival and eradication of 9-day established subcutaneous B16F10 melanomas in a proportion of mice. A series of survival studies in knockout mice supported a key mechanistic pathway, whereby TLR agonists acted via host cells to enhance IFN-γ production by adoptively transferred T cells. IFN-γ, in turn, enhanced the immunogenicity of the B16F10 melanoma line, leading to increased killing by adoptively transferred T cells. Thus, this combination approach counteracted tumor escape from immunotherapy via downregulation of immunogenicity. In conclusion, TLR agonists may represent advanced adjuvants within the setting of adoptive T-cell immunotherapy of cancer and hold promise as a safe means of enhancing this approach within the clinic.
authors.affiliation: Cancer Immunology Research Program, Peter MacCallum Cancer Centre, 14 St. Andrews Place, Melbourne, VIC 3002, Australia.
authors.forename: Sally M
authors.initials: SM
authors.lastname: Amos
authors.forename: Hollie J
authors.initials: HJ
authors.lastname: Pegram
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Westwood
authors.forename: Liza B
authors.initials: LB
authors.lastname: John
authors.forename: Christel
authors.initials: C
authors.lastname: Devaud
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Clarke
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kershaw
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D016219:Immunotherapy, Adoptive; D007249:Inflammation; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D011070:Poly I-C / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology*; D051193:Toll-Like Receptors / Q000819:agonists* / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D051193:Toll-Like Receptors; D007371:Interferon-gamma; D011070:Poly I-C