Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade.
Jeffrey J Ishizuka 1 2 3, Robert T Manguso 1 3, Collins K Cheruiyot 1 3, Kevin Bi 1 3, Arpit Panda 1 3 4, Arvin Iracheta-Vellve 1 3, Brian C Miller 1 2 3, Peter P Du 1 3, Kathleen B Yates 1 3, Juan Dubrot 1 3, Ilana Buchumenski 5, Dawn E Comstock 1 3 4, Flavian D Brown 1 3 4, Austin Ayer 1 3, Ian C Kohnle 1 3, Hans W Pope 1 3, Margaret D Zimmer 1 3, Debattama R Sen 1 3 4, Sarah K Lane-Reticker 1 3, Emily J Robitschek 1 3, Gabriel K Griffin 1 3 6, Natalie B Collins 1 3 7, Adrienne H Long 1 3, John G Doench 3, David Kozono 8, Erez Y Levanon 5, W Nicholas Haining 9 10 11
Most patients with cancer either do not respond to immune checkpoint blockade or develop resistance to it, often because of acquired mutations that impair antigen presentation. Here, we show that the loss of function of the RNA-editing enzyme ADAR1 in tumor cells profoundly sensitizes tumors to immunotherapy and overcomes resistance to checkpoint blockade. In the absence of ADAR1, A-to-I editing of interferon-inducible RNA species is reduced, leading to double-stranded RNA ligand sensing by PKR and MDA5; this results in growth inhibition and tumor inflammation, respectively. Loss of ADAR1 overcomes resistance to PD-1 checkpoint blockade caused by inactivation of antigen presentation by tumor cells. Thus, effective anti-tumor immunity is constrained by inhibitory checkpoints such as ADAR1 that limit the sensing of innate ligands. The induction of sufficient inflammation in tumors sensitized to interferon can bypass the therapeutic requirement for CD8+ T cell recognition of cancer cells and may provide a general strategy to overcome immunotherapy resistance.
Conflict of interest statement
Competing interests: This work was partly supported by Calico Life Sciences, LLC funding. J.J.I., R.T.M., and W.N.H. are authors of a patent application related to ADAR. W.N.H. consults for and has equity in Tango Therapeutics.