Although
immune checkpoint blockade (ICB) has strong clinical benefit for treating some
tumor types, it fails in others, indicating a need for additional modalities to enhance the ICB effect. Here, we identified one such modality by using DNA damage to create a live, injured
tumor cell adjuvant. Using an optimized ex vivo coculture system, we found that treating
tumor cells with specific concentrations of
etoposide,
mitoxantrone, or
doxorubicin markedly enhanced dendritic cell–mediated T cell activation. These immune-enhancing effects of DNA damage did not correlate with immunogenic cell death markers or with the extent of apoptosis or necroptosis; instead, these effects were mediated by live injured cells with activation of the
DNA-PK, ATR, NF-κB,
p38 MAPK, and RIPK1 signaling pathways. In mice, intratumoral injection of ex vivo etoposide–treated
tumor cells in combination with systemic ICB (by anti-PD-1 and anti-CTLA4
antibodies) increased the number of intratumoral CD103+ dendritic cells and circulating
tumor-antigen–specific CD8+ T cells, decreased
tumor growth, and improved survival. These effects were absent in Batf3−/− mice and in mice in which the
DNA-damaging drug was injected directly into the
tumor, due to DNA damage in the immune cells. The combination treatment induced complete
tumor regression in a subset of mice that were then able to reject
tumor rechallenge, indicating that the injured cell adjuvant treatment induced durable antitumor immunological memory. These results provide a strategy for enhancing the efficacy of
immune checkpoint inhibition in
tumor types that do not respond to this treatment modality by itself.