Endogenous dendritic cells (DC) cross-present cancer antigens in “hot” tumors, recruit CD8+ cytotoxic T cells (CTL) and support CTL survival and functions, being critical to the effectiveness of PD-1 blockade and other therapies. Local injections of ex-vivo-generated DCs have been used to overcome PD1-resistance of “cold” tumors lacking endogenous cDC1s, but their effectiveness and mechanism of action remain unclear.
Here, we report that a single intratumoral injection of short-term-activated, but not fully mature cDC1-like DC induced by interferons, dsRNA and other mediators of anti-viral immunity, is sufficient to sensitize nominally PD1-resistant cancers (mouse breast, ovarian, colon, and pediatric sarcoma models) to PD1 blockade, eliciting CD8+ T cell-dependent systemic immunity, complete tumor regressions and resistance to tumor rechallenge. Locally injected cDC1 are sufficient to enhance the intratumoral numbers of CD8+ T-cells and their polyfunctionality, but only their combination with PD1 blockade induces effector CTL phenotypes characterized by low TCF1/7, CD44 and BLIMP-1, and high Granzyme B/Ki67/PD-1 levels. The PD1-sensitizing activity of cDC1 does not require their ex vivo loading with tumor antigens, DC BATF3 expression or their BATF3-dependent production of IL-12p70 but it is lost in CXCL10 (IP10)-deficient cDC1s and elevated in very short-term-activated cDC1s which produce particularly high levels of CXCL10.
Dependence of local/intratumoral DC therapies on the DCs chemokine-producing function, rather than IL-12p70, indicates that the paradigms derived from DC vaccines have limited applicability to local/intratumoral DC treatments and challenges the status of mature DC as “gold standard” of DC therapies.