Pharmacological rescue of tumor intrinsic STING expression and immune response in LKB1-mutant lung cancer via the IAP-JAK regulatory axis

Shu, C.; Jin, R.; Niu, Q.; Cicka, D.; Doyle, S.; Wahafu, A.; Fan, D.; Zheng, X.; Du, Y.; Ivanov, A.; Doxie, D.; Dhodapkar, K.; Carlisle, J.; Owonikoko, T.; Ramalingam, S.; Sica, G.; Dhodapkar, M.; Zhou, W.; Mo, X.; Fu, H.

doi:10.1101/2021.09.17.460294

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bioRxiv · 10.1101/2021.09.17.460294

Pharmacological rescue of tumor intrinsic STING expression and immune response in LKB1-mutant lung cancer via the IAP-JAK regulatory axis

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Abstract

Harnessing the power of the immune system to treat cancer has become a core clinical approach. However, rewiring of intrinsic circuitry enables tumor cells to escape immune attacks, leading to therapeutic failure. Pharmacological strategies to reverse tumor genotype-dictated therapeutic resistance are urgently needed to advance precision immunotherapy. Here, we identify antagonists of Inhibitor of Apoptosis Protein (IAP) as potent sensitizers that restore immune-dependent killing of LKB1-mutant lung cancer cells. Mechanistic studies reveal an LKB1-IAP-JAK trimolecular complex that bridges the LKB1-mutant genotype with IAP-dependency and a STING-deficiency-mediated immune resistance phenotype. Ultimately, inhibition of IAP re-establishes JAK-regulated STING expression and DNA sensing pathway as well as enhanced cytotoxic immune cell infiltration and selective immune-dependent anti-tumor activity in an LKB1-mutant immune-competent mouse model. Thus, IAP-JAK-modulatory strategies, like IAP inhibitors, offer promising immunotherapy adjuvants to re-establish the responsiveness of "immunologically-cold" LKB1-mutant tumors to immune checkpoint inhibitors or STING-directed therapies.

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Shu, C., Jin, R., Niu, Q., Cicka, D., Doyle, S., Wahafu, A., Fan, D., Zheng, X., Du, Y., Ivanov, A., Doxie, D., Dhodapkar, K., Carlisle, J., Owonikoko, T., Ramalingam, S., Sica, G., Dhodapkar, M., Zhou, W., Mo, X., Fu, H.. 2021-09-17. Pharmacological rescue of tumor intrinsic STING expression and immune response in LKB1-mutant lung cancer via the IAP-JAK regulatory axis. https://doi.org/10.1101/2021.09.17.460294

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