The differences in function, location, and migratory pattern of conventional dendritic cells (cDC) and plasmacytoid DCs (pDC) not only point to specialized roles in immune responses but also signify additive and interdependent relationships required to clear pathogens. We studied the in vivo requirement of cross-talk between
cDCs and pDCs for eliciting antitumor immunity against in situ released
tumor antigens in the absence or presence of the
Toll-like receptor (TLR) 9 agonist CpG. Previous data indicated that CpG boosted
tumor-specific T-cell responses after in vivo
tumor destruction and increased survival after
tumor rechallenges. The present study shows that
cDCs are indispensable for cross-presentation of ablation-released
tumor antigens and for the induction of long-term antitumor immunity. Depletion of pDCs or applying this model in type I IFN receptor-deficient mice abrogated CpG-mediated responses. CD8α(+)
cDCs and the recently identified merocytic
cDCs were dependent on pDCs for CpG-induced upregulation of CD80. Moreover, DC transfer studies revealed that merocytic
cDCs and CD8α(+)
cDCs were most susceptible to pDC help and subsequently promoted
tumor-free survival in a therapeutic setting. By transferring wild-type pDCs into TLR9-deficient mice, we finally showed that TLR9 expression in pDCs is sufficient to benefit from CpG as an adjuvant. These studies indicate that the efficacy of CpG in
cancer immunotherapy is dependent on cross-talk between pDCs and specific subsets of
cDCs.