Damage response to DNA damage in living tumor cells promotes anti-tumor immunity

October 19, 2021.

-Vol. 14, No. 705

Volume 14, Issue 705

-.

DOI: 10.1126 / scisignal.abc4764

Commentary

Immune checkpoint inhibition (ICB) in cancer therapy has been shown to have powerful clinical benefits for some tumor types, but fails for others, indicating that additional modalities are needed to enhance ICB efficacy.

In this study, we have identified one such modality by using DNA damage to create a living but damaged tumor cell adjuvant.

Using an optimized exvivo co-culture system, they observed that treatment of tumor cells with specific concentrations of etoposide, mitoxantrone, and doxorubicin significantly enhanced dendritic cell-mediated T cell activation.

These immune-enhancing effects of DNA damage have not been shown to correlate with immunogenic cell death markers or the degree of apoptosis or necroptosis.

Instead, they have been shown to be mediated by living damaged cells with activation of DNA-PK, ATR, NF-κB, p38 MAPK, and RIPK1 signaling pathways.

Experiments in mice showed + dendritic cells and circulating tumor antigen-specific CD8 + T cells, reduced tumor growth, and improved survival; these effects were not seen in Batf3 -/- mice or in mice in which DNA-damaging drugs were injected directly into tumors due to DNA damage in immune cells.

The combination treatment was able to induce complete tumor regression in a subset of mice and then reject tumor rechallenge, indicating that the damaged cell adjuvant treatment induced a lasting anti-tumor immune memory.

These results indicate that it may provide a strategy to increase the efficacy of immune checkpoint inhibition in tumor types that do not respond to this treatment by themselves.