Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells
Barbara Drobits, … , Marco Colonna, Maria Sibilia
Barbara Drobits, … , Marco Colonna, Maria Sibilia
Published January 17, 2012
Citation Information: J Clin Invest. 2012;122(2):575-585. https://doi.org/10.1172/JCI61034.
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Research Article

Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells

Abstract

Imiquimod is a synthetic compound with antitumor properties; a 5% cream formulation is successfully used to treat skin tumors. The antitumor effect of imiquimod is multifactorial, although its ability to modulate immune responses by triggering TLR7/8 is thought to be key. Among the immune cells suggested to be involved are plasmacytoid DCs (pDCs). However, a direct contribution of pDCs to tumor killing in vivo and the mechanism of their recruitment to imiquimod-treated sites have never been demonstrated. Using a mouse model of melanoma, we have now demonstrated that pDCs can directly clear tumors without the need for the adaptive immune system. Topical imiquimod treatment led to TLR7-dependent and IFN-α/β receptor 1–dependent (IFNAR1-dependent) upregulation of expression of the chemokine CCL2 in mast cells. This was essential to induce skin inflammation and for the recruitment of pDCs to the skin. The recruited pDCs were CD8α+ and induced tumor regression in a TLR7/MyD88- and IFNAR1-dependent manner. Lack of TLR7 and IFNAR1 or depletion of pDCs or CD8α+ cells from tumor-bearing mice completely abolished the effect of imiquimod. TLR7 was essential for imiquimod-stimulated pDCs to produce IFN-α/β, which led to TRAIL and granzyme B secretion by pDCs via IFNAR1 signaling. Blocking these cytolytic molecules impaired pDC-mediated tumor killing. Our results demonstrate that imiquimod treatment leads to CCL2-dependent recruitment of pDCs and their transformation into a subset of killer DCs able to directly eliminate tumor cells.

Authors

Barbara Drobits, Martin Holcmann, Nicole Amberg, Melissa Swiecki, Roland Grundtner, Martina Hammer, Marco Colonna, Maria Sibilia

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Figure 5

pDCs are responsible for the tumoricidal effect of Imi.

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pDCs are responsible for the tumoricidal effect of Imi. (A) Graph demons...
(A) Graph demonstrating the absence of pDCs (CD11c+B220+SiglecH+) in spleen and tumor draining lymph nodes of Bdca2-DTR mice depleted of pDCs by DT injection (+DT). Control (not pDC-depleted) mice were injected with PBS. (B) Relative tumor growth in pDC-depleted mice treated with Imi. Bdca2-DTR transgenic mice were depleted of pDCs prior to intradermal injection of B16-F10 cells (n = 5–7 per group). (C and D) FACS analysis showing the percentage of monocytes/neutrophils (CD11b+), CD4+ T cells (CD3+CD4+), CD8α+ T cells (CD3+CD8α+), and NK cells (NK1.1+) in (C) tumor-draining lymph nodes and (D) tumor-infiltrating CD8α+ DCs in Bdca2-DTR mice treated as indicated. (E) Quantification of the active caspase-3–positive area (μm2 per mm2 of tumors) in tumor tissue of WT (n = 7–8 per group), pDC-depleted (pDCs depl.) (n = 8–9), and Tlr7–/– (n = 3) mice treated with Imi or left untreated. The active caspase-3+ area was analyzed in 10 randomly chosen fields of at least 3 independent samples. *P < 0.05, **P < 0.005.