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: Sally M Amos, Hollie J Pegram, Jennifer A Westwood, Liza B John, Christel Devaud, Chris J Clarke, Nicholas P Restifo, Mark J Smyth, Phillip K Darcy, Michael H Kershaw
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 60 Issue 5 Pg. 671-83 (May 2011) ISSN: 1432-0851 [Electronic] Germany
• PMID: 21327636 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• CPG-oligonucleotide
• Oligodeoxyribonucleotides
• Toll-Like Receptors
• Interferon-gamma
• Poly I-C

Topics

• Adjuvants, Immunologic (administration & dosage)
• Animals
• Cell Line, Tumor
• Dendritic Cells (immunology)
• Flow Cytometry
• Immunotherapy, Adoptive
• Inflammation
• Interferon-gamma (biosynthesis)
• Lymphocyte Activation
• Melanoma, Experimental (immunology, therapy)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Oligodeoxyribonucleotides (therapeutic use)
• Poly I-C (therapeutic use)
• T-Lymphocytes (immunology)
• Toll-Like Receptors (agonists, immunology)