The TLR-7 agonist, imiquimod, enhances dendritic cell survival and promotes tumor antigen-specific T cell priming: relation to central nervous system antitumor immunity.
Immunotherapy represents an appealing option to specifically target CNS tumors using the immune system. In this report, we tested whether adjunctive treatment with the TLR-7 agonist imiquimod could augment antitumor immune responsiveness in CNS tumor-bearing mice treated with human gp100 + tyrosine-related protein-2 melanoma-associated Ag peptide-pulsed dendritic cell (DC) vaccination. Treatment of mice with 5% imiquimod resulted in synergistic reduction in CNS tumor growth compared with melanoma-associated Ag-pulsed DC vaccination alone. Continuous imiquimod administration in CNS tumor-bearing mice, however, was associated with the appearance of robust innate immune cell infiltration and hemorrhage into the brain and the tumor. To understand the immunological mechanisms by which imiquimod augmented antitumor immunity, we tested whether imiquimod treatment enhanced DC function or the priming of tumor-specific CD8+ T cells in vivo. With bioluminescent, in vivo imaging, we determined that imiquimod dramatically enhanced both the persistence and trafficking of DCs into the draining lymph nodes after vaccination. We additionally demonstrated that imiquimod administration significantly increased the accumulation of tumor-specific CD8+ T cells in the spleen and draining lymph nodes after DC vaccination. The results suggest that imiquimod positively influences DC trafficking and the priming of tumor-specific CD8+ T cells. However, inflammatory responses induced in the brain by TLR signaling must also take into account the local microenvironment in the context of antitumor immunity to induce clinical benefit. Nevertheless, immunotherapeutic targeting of malignant CNS tumors may be enhanced by the administration of the innate immune response modifier imiquimod.
Prins
Robert M
RM
Division of Neurosurgery, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA 90095, USA. rprins@mednet.ucla.edu
Craft
Noah
N
Bruhn
Kevin W
KW
Khan-Farooqi
Haumith
H
Koya
Richard C
RC
Stripecke
Renata
R
Miller
Jeff F
JF
Liau
Linda M
LM
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D019264:Adoptive Transfer; D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D002470:Cell Survival / Q000187:drug effects; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D021621:Imaging, Three-Dimensional; D000077271:Imiquimod; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000556:secondary; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D009363:Neoplasm Proteins / Q000276:immunology; D009368:Neoplasm Transplantation; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D058951:gp100 Melanoma Antigen
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; C548642:Pmel protein, mouse; D058951:gp100 Melanoma Antigen; D000077271:Imiquimod