Tumoricidal Activity of TLR7/8-activated Inflammatory Dendritic Cells

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2007 May 31

PMID 17535975

Citations 151

Authors

Georg Stary

Christine Bangert

Martina Tauber

Robert Strohal

Tamara Kopp

Georg Stingl

Affiliations

Soon will be listed here.

Abstract

Imiquimod (IMQ), a synthetic agonist to Toll-like receptor (TLR) 7, is being successfully used for the treatment of certain skin neoplasms, but the exact mechanisms by which this compound induces tumor regression are not yet understood. While treating basal cell carcinoma (BCC) patients with topical IMQ, we detected, by immunohistochemistry, sizable numbers of both myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs) within the inflammatory infiltrate. Surprisingly, peritumoral mDCs stained positive for perforin and granzyme B, whereas infiltrating pDCs expressed tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The biological relevance of this observation can be deduced from our further findings that peripheral blood-derived CD11c(+) mDCs acquired antiperforin and anti-granzyme B reactivity upon TLR7/8 stimulation and could use these molecules to effectively lyse major histocompatibility complex (MHC) class I(lo) cancer cell lines. The same activation protocol led pDCs to kill MHC class I-bearing Jurkat cells in a TRAIL-dependent fashion. While suggesting that mDCs and pDCs are directly involved in the IMQ-induced destruction of BCC lesions, our data also add a new facet to the functional spectrum of DCs, ascribing to them a major role not only in the initiation but also in the effector phase of the immune response.

Citing Articles

Advances in targeted delivery of mRNA into immune cells for enhanced cancer therapy.

Huang L, Huang Z, Zhang Y, Lin C, Zhao Z, Li R Theranostics. 2024; 14(14):5528-5550.

PMID: 39310113 PMC: 11413781. DOI: 10.7150/thno.93745.

Plasmacytoid dendritic cells at the forefront of anti-cancer immunity: rewiring strategies for tumor microenvironment remodeling.

Monti M, Ferrari G, Gazzurelli L, Bugatti M, Facchetti F, Vermi W J Exp Clin Cancer Res. 2024; 43(1):196.

PMID: 39020402 PMC: 11253500. DOI: 10.1186/s13046-024-03121-9.

Immune mediated support of metastasis: Implication for bone invasion.

Xin Z, Qin L, Tang Y, Guo S, Li F, Fang Y Cancer Commun (Lond). 2024; 44(9):967-991.

PMID: 39003618 PMC: 11492328. DOI: 10.1002/cac2.12584.

Blastic Plasmacytoid Dendritic Cell Neoplasm, from a Dermatological Point of View.

Di Raimondo C, Lozzi F, Di Domenico P, Paganini C, Campione E, Galluzzo M Int J Mol Sci. 2024; 25(13).

PMID: 39000208 PMC: 11240932. DOI: 10.3390/ijms25137099.

The Multifaceted Functionality of Plasmacytoid Dendritic Cells in Gastrointestinal Cancers: A Potential Therapeutic Target?.

Hansen F, David P, Weber G Cancers (Basel). 2024; 16(12).

PMID: 38927922 PMC: 11201847. DOI: 10.3390/cancers16122216.

References

Tucker S, Polasek J, Perri A, Goldsmith E . Long-term follow-up of basal cell carcinomas treated with perilesional interferon alfa 2b as monotherapy. J Am Acad Dermatol. 2006; 54(6):1033-8. DOI: 10.1016/j.jaad.2006.02.035. View

Wiley S, Schooley K, Smolak P, Din W, Huang C, Nicholl J . Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995; 3(6):673-82. DOI: 10.1016/1074-7613(95)90057-8. View

Medzhitov R, Preston-Hurlburt P, Janeway Jr C . A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997; 388(6640):394-7. DOI: 10.1038/41131. View

Mocellin S, Provenzano M, Lise M, Nitti D, Rossi C . Increased TIA-1 gene expression in the tumor microenvironment after locoregional administration of tumor necrosis factor-alpha to patients with soft tissue limb sarcoma. Int J Cancer. 2003; 107(2):317-22. DOI: 10.1002/ijc.11369. View

Wang S, El-Deiry W . TRAIL and apoptosis induction by TNF-family death receptors. Oncogene. 2003; 22(53):8628-33. DOI: 10.1038/sj.onc.1207232. View

Sullivan T, Dearaujo T, Vincek V, Berman B . Evaluation of superficial basal cell carcinomas after treatment with imiquimod 5% cream or vehicle for apoptosis and lymphocyte phenotyping. Dermatol Surg. 2004; 29(12):1181-6. DOI: 10.1111/j.1524-4725.2003.29399.x. View

Grebenova D, Kuzelova K, Fuchs O, Halada P, Havlicek V, Marinov I . Interferon-alpha suppresses proliferation of chronic myelogenous leukemia cells K562 by extending cell cycle S-phase without inducing apoptosis. Blood Cells Mol Dis. 2004; 32(1):262-9. DOI: 10.1016/j.bcmd.2003.10.008. View

Diebold S, Kaisho T, Hemmi H, Akira S, Reis e Sousa C . Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004; 303(5663):1529-31. DOI: 10.1126/science.1093616. View

Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S . Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004; 303(5663):1526-9. DOI: 10.1126/science.1093620. View

10.

Akira S, Takeda K . Toll-like receptor signalling. Nat Rev Immunol. 2004; 4(7):499-511. DOI: 10.1038/nri1391. View

11.

Palamara F, Meindl S, Holcmann M, Luhrs P, Stingl G, Sibilia M . Identification and characterization of pDC-like cells in normal mouse skin and melanomas treated with imiquimod. J Immunol. 2004; 173(5):3051-61. DOI: 10.4049/jimmunol.173.5.3051. View

12.

Fleming C, Bryden A, Evans A, Dawe R, Ibbotson S . A pilot study of treatment of lentigo maligna with 5% imiquimod cream. Br J Dermatol. 2004; 151(2):485-8. DOI: 10.1111/j.1365-2133.2004.05983.x. View

13.

Smith K, Hamza S, Skelton H . Topical imidazoquinoline therapy of cutaneous squamous cell carcinoma polarizes lymphoid and monocyte/macrophage populations to a Th1 and M1 cytokine pattern. Clin Exp Dermatol. 2004; 29(5):505-12. DOI: 10.1111/j.1365-2230.2004.01593.x. View

14.

Theos A, Cummins R, Silverberg N, Paller A . Effectiveness of imiquimod cream 5% for treating childhood molluscum contagiosum in a double-blind, randomized pilot trial. Cutis. 2004; 74(2):134-8, 141-2. View

15.

Michalopoulos P, Yawalkar N, Bronnimann M, Kappeler A, Braathen L . Characterization of the cellular infiltrate during successful topical treatment of lentigo maligna with imiquimod. Br J Dermatol. 2004; 151(4):903-6. DOI: 10.1111/j.1365-2133.2004.06176.x. View

16.

SIDKY Y, Borden E, Weeks C, Reiter M, Hatcher J, Bryan G . Inhibition of murine tumor growth by an interferon-inducing imidazoquinolinamine. Cancer Res. 1992; 52(13):3528-33. View

17.

Weeks C, Gibson S . Induction of interferon and other cytokines by imiquimod and its hydroxylated metabolite R-842 in human blood cells in vitro. J Interferon Res. 1994; 14(2):81-5. DOI: 10.1089/jir.1994.14.81. View

18.

Yawalkar N, Hunger R, Buri C, Schmid S, Egli F, Brand C . A comparative study of the expression of cytotoxic proteins in allergic contact dermatitis and psoriasis: spongiotic skin lesions in allergic contact dermatitis are highly infiltrated by T cells expressing perforin and granzyme B. Am J Pathol. 2001; 158(3):803-8. PMC: 1850348. DOI: 10.1016/S0002-9440(10)64027-8. View

19.

Kadowaki N, Ho S, Antonenko S, Malefyt R, Kastelein R, Bazan F . Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med. 2001; 194(6):863-9. PMC: 2195968. DOI: 10.1084/jem.194.6.863. View

20.

Vanderheyde N, Aksoy E, Amraoui Z, Vandenabeele P, Goldman M, Willems F . Tumoricidal activity of monocyte-derived dendritic cells: evidence for a caspase-8-dependent, Fas-associated death domain-independent mechanism. J Immunol. 2001; 167(7):3565-9. DOI: 10.4049/jimmunol.167.7.3565. View