Lots of exciting hints from our bulk and single-cell RNA-sequencing which is giving is very exciting clues about how TBK1 regulates not only the tumor cells, but in turn may be able to tweak the immune system in ways that may make cancer immunotherapy more effective. The experiments were the easy part! Now for the complex data analysis evaluating changes in thousands of genes. Now is the time for the computational biologists to shine!
Big development! We just started analyzing data from our big, single-cell RNA-sequencing experiment in which we seek to understand the changes in tumors with and without functional TANK-binding kinase 1 (TBK1). It's still early, but it looks like we have some very interesting changes!
Initial hints from gene expression profiling using RNA-sequencing are suggesting that cells lacking TBK1 have altered responses to inflammation, perhaps making them more susceptible to attack by the immune system! Still more work to do, but the early evidence is pretty convincing. We're still not certain which signaling pathways are active/impaired in cell lacking TBK1 in these conditions, but our hope is that gene expression profiling will nominate a few candidate pathways for us to explore further.
Despite the unprecedented success of immune checkpoint blockade (ICB) in melanoma and other cancers, tackling innate (primary) resistance remains a major challenge and robust biomarkers to guide treatment are lacking. Clinical trials are already underway evaluating novel immune modulatory agents in combination with anti-PD-1/PD-L1 therapies in an effort to overcome innate resistance. Despite increasing reports of ‘rational’ combination strategies, these therapies remain “one size fits all”, due the lack of robust biomarkers to guide clinical decision-making. Given the recent failures of several initially high-profile phase III combination immunotherapy trials coupled with the ever-increasing number of novel therapies and combination trials, there is an unmet need for novel approaches, tools, techniques, and methods for pre-clinical and clinical use to better understand mechanisms of response and resistance to immune checkpoint inhibitors and next-generation anti-tumor immune modulatory drugs.
A major focus of my lab's research is the protein, TANK-binding kinase 1 (TBK1). TBK1 is a Ser/Thr kinase involved in innate immune signaling and is an emerging target for anti-cancer therapy. Importantly, independent orthogonal data from two different laboratories has also identified TBK1 as a cancer immunotherapy target. This project aims to investigate TBK1 as a novel cancer immunotherapy target to overcome resistance to PD-1 blockade by reprogramming the tumor microenvironment. Several key research efforts are underway and we hope to have more exciting data to share soon!