DPP9-mediated inflammasome repression protects against checkpoint inhibitor lung toxicity

Brewer, J. R.; Han, A.; Nassar, A. H.; Farhat, E. B.; Blackburn, H. N.; Xiao, T.; Mirza, H.; Mowel, W. K.; Sefik, E.; Hartner, S.; Chiorazzi, M.; Itoh, T.; Oh, M.-H.; Madden, M. Z.; Rangavajhula, A.; Adib, E.; Saleh, M. J.; Machaalani, M.; Rakaee, M.; Tafavvoghi, M.; Quattropani, C.; Gazetos, N.; Gerber, D.; Fattah, F.; SoRelle, J. A.; Choo, D.; von Itzstein, M. S.; Bevans-Fonti, S.; Ghanbar, M.; Suresh, K.; Mazumder, T.; Ye, C. J.; Choueiri, T. K.; Gusev, A.; Flavell, R. A.

doi:10.64898/2026.06.30.735609

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bioRxiv · 10.64898/2026.06.30.735609

DPP9-mediated inflammasome repression protects against checkpoint inhibitor lung toxicity

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Abstract

Over one million patients receive cancer immunotherapy annually, yet the mechanisms underlying life-threatening immune-mediated toxicities remain poorly understood. Checkpoint inhibitor pneumonitis (CIP) is the leading cause of immunotherapy-related mortality, with a case fatality rate approaching 10%, and no genetic risk factors have been described to date. We identified Dipeptidyl-peptidase 9 (DPP9) as the first genetic susceptibility gene for CIP in a clinico-genomics cohort of 4,397 patients treated with immune checkpoint inhibitors. Mechanistically, DPP9 suppresses CARD8 inflammasome activation and IL-18 secretion in human monocytes, a pathway which is engaged prior to CIP onset, with IL-18 selectively elevated in the plasma of patients who subsequently develop CIP. Myeloid-restricted ablation of Dpp8 and Dpp9 in mice recapitulated the pulmonary histopathological and immunological hallmarks of CIP, including granuloma formation, accumulation of IFN{gamma}-producing T cells and monocyte-derived macrophages. Each of these phenotypes were driven by excessive IL-18 secretion. Together, these findings establish DPP9 as a genetic determinant of CIP and nominate IL-18 blockade as a mechanistically rational therapeutic strategy.

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Brewer, J. R., Han, A., Nassar, A. H., Farhat, E. B., Blackburn, H. N., Xiao, T., Mirza, H., Mowel, W. K., Sefik, E., Hartner, S., Chiorazzi, M., Itoh, T., Oh, M.-H., Madden, M. Z., Rangavajhula, A., Adib, E., Saleh, M. J., Machaalani, M., Rakaee, M., Tafavvoghi, M., Quattropani, C., Gazetos, N., Gerber, D., Fattah, F., SoRelle, J. A., Choo, D., von Itzstein, M. S., Bevans-Fonti, S., Ghanbar, M., Suresh, K., Mazumder, T., Ye, C. J., Choueiri, T. K., Gusev, A., Flavell, R. A.. 2026-07-03. DPP9-mediated inflammasome repression protects against checkpoint inhibitor lung toxicity. https://doi.org/10.64898/2026.06.30.735609

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