Abstract
In addition to local cytotoxic activity, radiotherapy may also elicit local and systemic antitumor immunity, which may be augmented by immunotherapeutic agents including Toll-like receptor (TLR) 7/8 agonists. Here, we investigated the ability of 3M-011 (854A), a TLR7/8 agonist, to boost the antigen-presenting activity of dendritic cells (DC) as an adjuvant to radiotherapy. The combined treatment induced marked local and systemic responses in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer. In vitro cytotoxicity assays as well as in vivo depletion experiments with monoclonal antibodies identified NK and CD8 T cells as the cell populations mediating the cytotoxic effects of the treatment, while in vivo depletion of CD11c+ dendritic cells (DC) in CD11c-DTR transgenic mice revealed DC as the pivotal immune hub in this setting. The specificity of the immune reaction was confirmed by ELISPOT assays. TLR7/8 agonists therefore seem to be potent adjuvants to radiotherapy, inducing strong local and profound systemic immune responses to tumor antigens released by conventional therapy.
Highlights
While considerable progress has been made in the therapy of colorectal cancer (CRC), the prognosis of metastatic CRC is still often unfavorable [1]
As previous reports had indicated an involvement of Toll-like receptor (TLR) signaling in tumorigenesis [17], we first evaluated the effects of the TLR7/8 agonist on various tumor cell lines
CD11c+ dendritic cell-mediated NK and T-cell priming is required for the effects of the treatment combination. Since both CD8 T cells and NK cells are dependent on previous activation by antigen-presenting cells such as dendritic cells (DC), we aimed to investigate the role of DC by selectively depleting these cells in tumor-bearing and treated mice
Summary
While considerable progress has been made in the therapy of colorectal cancer (CRC), the prognosis of metastatic CRC is still often unfavorable [1]. Traditional systemic therapies are often unable to eradicate all tumor cells and usually cannot provide a cure. Among the currently most successfully used www.impactjournals.com/oncotarget immunotherapeutics are imidazoquinoline derivatives, most notably imiquimod (Aldara® cream), a selective TLR7 agonist, which can be topically used in malignant and premalignant skin lesions and shows considerable response rates [3]. Upon antigen contact and TLR activation, these cells show increased proliferation, cytokine secretion, costimulatory molecule expression, phagocytic activity and antigen presentation [4]. The agent used in the present work, 3M011, an agonist for TLR7/8, is soluble in aqueous buffers and can be administered systemically [5,6]. The agent used in the present work, 3M011, an agonist for TLR7/8, is soluble in aqueous buffers and can be administered systemically [5,6]. 3M011 does not activate mouse TLR8, acting as a TLR7 agonist only in the murine setting [5]
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