Targeting TBK1 to overcome resistance to cancer immunotherapy

Abstract

<p>Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking<a title="Jenkins, R. W., Barbie, D. A. & Flaherty, K. T. Mechanisms of resistance to immune checkpoint inhibitors. Br. J. Cancer 118, 9–16 (2018)." href="https://www.nature.com/articles/s41586-023-05704-6#ref-CR1">1</a>,<a title="Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017)." href="https://www.nature.com/articles/s41586-023-05704-6#ref-CR2">2</a>. Here we identify the innate immune kinase TANK-binding kinase 1 (<em>TBK1</em>)<a title="Zhou, R., Zhang, Q. & Xu, P. TBK1, a central kinase in innate immune sensing of nucleic acids and beyond. Acta Biochim. Biophys. Sin. 52, 757–767 (2020)." href="https://www.nature.com/articles/s41586-023-05704-6#ref-CR3">3</a> as a candidate immune-evasion gene in a pooled genetic screen<a title="Manguso, R. T. et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 547, 413–418 (2017)." href="https://www.nature.com/articles/s41586-023-05704-6#ref-CR4">4</a>. Using a suite of genetic and pharmacological tools across multiple experimental model systems, we confirm a role for <em>TBK1</em> as an immune-evasion gene. Targeting TBK1 enhances responses to PD-1 blockade by decreasing the cytotoxicity threshold to effector cytokines (TNF and IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumour models, with concordant findings in matched patient-derived organotypic tumour spheroids and matched patient-derived organoids. Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNF and IFNγ in a JAK–STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is an effective strategy to overcome resistance to cancer immunotherapy.</p>