TY - JOUR
T1 - Adoptive immunotherapy combined with intratumoral TLR agonist delivery eradicates established melanoma in mice
AU - Amos, Sally M
AU - Pegram, Hollie J
AU - Westwood, Jennifer A
AU - John, Liza B
AU - Devaud, Christel
AU - Clarke, Chris J P
AU - Restifo, Nicholas P
AU - Smyth, Mark J
AU - Darcy, Phillip K
AU - Kershaw, Michael H
PY - 2011
Y1 - 2011
N2 - 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-gamma production by adoptively transferred T cells. IFN-gamma, 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.
AB - 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-gamma production by adoptively transferred T cells. IFN-gamma, 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.
UR - http://www.springerlink.com/content/9814v711361p5344/fulltext.pdf
U2 - 10.1007/s00262-011-0984-8
DO - 10.1007/s00262-011-0984-8
M3 - Article
SN - 0340-7004
VL - 60
SP - 671
EP - 683
JO - Cancer Immunology Immunotherapy
JF - Cancer Immunology Immunotherapy
IS - 5
ER -
