Melanoma-induced suppression of Dendritic Cells (DC) in the Sentinel Lymph Node (SLN) interferes with the generation of protective anti-tumor immunity. In an effort to strengthen immune defenses against metastatic spread, 28 Stage I-III melanoma patients were randomized in a 3-arm Phase-II study to receive i.d. injections around the primary tumor excision site of saline or low-dose CpG-B, alone or combined with GM-CSF, prior to excision of the SLN. Combined CpG/GM-CSF administration resulted in enhanced maturation of all identifiable conventional (cDC) and plasmacytoid (pDC) DC subsets and selectively induced increased frequencies of SLN-resident BDCA3/CD141+ cDC subsets that also expressed the C-type Lectin Receptor CLEC9A. Correlative in vivo analyses and in vitro studies provided evidence that these subsets were derived from BDCA3+ cDC precursors in the blood that were recruited to the SLN in a type-1 interferon-dependent manner and subsequently matured under the combined influence of CpG and GM-CSF. In line with their reported functional abilities, frequencies of in vivo CpG/GM-CSF-induced BDCA3/CD141+ DC correlated with increased ex vivo cross-presenting capacity of SLN suspensions. Combined local CpG/GM-CSF delivery thus supports protective anti-melanoma immunity through concerted activation of pDC and cDC subsets and recruitment of BDCA3+ cDC subsets with T cell-stimulatory and cross-priming abilities.
- Received September 4, 2014.
- Revision received January 9, 2015.
- Accepted January 22, 2015.
- Copyright © 2015, American Association for Cancer Research.