A lack of response to immunotherapy is an ongoing challenge in cancer treatment. An intense focus of study is to find a workaround for patients’ cancer cells that are unaffected by the drugs or develop resistance during treatment. Now, investigators have discovered that cancer cells’ expression of an immune evasion gene—TANK-binding kinase 1 (TBK1)—may allow the cells to be unaffected by immunotherapy or develop resistance during treatment. Further, they found that silencing TBK1, or blocking its expressed protein, enhanced cancer cells’ susceptibility to immunotherapy in multiple preclinical models.

This work is published in Nature in the paper, “Targeting TBK1 to overcome resistance to cancer immunotherapy.

The innate immune kinase TANK-binding kinase 1 (TBK1) was identified as a candidate immune evasion gene in a pooled genetic screen. TBK1 is a multi-functional enzyme with an established role in coordinating innate immune responses to viruses and other invading pathogens. In addition, mouse studies have previously shown that treatment with a pharmacologic inhibitor that blocks the activity of the TBK1 protein overcame tumors’ resistance to immunotherapy, without causing weight loss or other signs of systemic toxicity.

TBK1 inhibition in combination with PD-1 blockade, the authors noted, also demonstrated efficacy using patient-derived tumor models, with concordant findings in matched patient-derived organotypic tumor spheroids (PDOTS) and matched patient-derived organoids (PDOs).

The team found that blocking TBK1 augments the response to immunotherapy by sensitizing tumor cells to the effects of immune molecules including tumor necrosis factor and interferon. More specifically, targeting TBK1 enhances response to PD-1 blockade by lowering the cytotoxicity threshold to effector cytokines (TNFα/IFNγ). Tumor cells lacking TBK1, they noted, “are primed to undergo RIPK- and caspase-dependent cell death in response to TNFα/IFNγ in a JAK/STAT-dependent manner.”

“It’s counterintuitive that TBK1 loss would enhance immunotherapy because this protein is generally thought to promote inflammation. Turning it off should make a tumor less sensitive to treatment, not more” said Robert Manguso, PhD, an investigator in the Center for Cancer Research at MGH, assistant professor of medicine at Harvard Medical School, who also co-leads the Tumor Immunotherapy Discovery Engine project at Broad. “However, we found that turning off TBK1 reprograms tumor cells’ response to immune signals called cytokines, causing them to die. This latter effect turns out to be critical in this context.”

“Our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome resistance to cancer immunotherapy,” said Russell Jenkins, MD, PhD, investigator in the Center for Cancer Research at MGH and an assistant professor of medicine at Harvard Medical School, and associate member of the Broad Institute. “Our work also provides a framework to evaluate other potential immune evasion targets across multiple model systems using a combination of genetic and pharmacologic tools.”

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