Restoring the Immunogenicity of Head and Neck Cancer

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PROJECT SUMMARY Immune checkpoint receptor blockade (ICB) has been approved recently for the treatment of metastatic, unresectable, or recurrent head and neck squamous cell carcinoma (HNC) in the first-line setting. Multiple priming strategies have entered into trials, aiming to turn cold HNCs, which account for about 85% of the cases, into T-cell inflamed hot tumors and expand the pool of patients who can benefit from immunotherapy. Mechanistically, many priming strategies activate innate immune sensors to launch the production of type-I interferons (IFN-I) by cancer cells and myeloid cells. The activation of IFN-I and its target genes promotes antigen-presenting cell (APC) and effector cell trafficking to the tumor bed and enhances APC cross-priming efficiency. A central converging point of the current priming approaches is an adaptor molecule located at the endoplasmic reticulum and its associated membranes, stimulator of interferon genes (STING). Lead cold tumor sensitization treatments, such as irradiation, inhibition of DNA damage repair, induction of DNA replication stress, and STING agonists all engage the STING pathway, further validating the promise of STING-priming in restoring the immunogenicity of cancers. However, recent trials of STING agonists showed a high resistance rate in patients with solid tumors, even in combination with ICB. The mechanism of HNC resistance to STING priming is poorly understood, and few strategies are available to overcome cancer resistance to innate immune sensing. The long-term goal of this program is to establish the biochemical and metabolic regulatory network of HNC immunogenicity and improve HNC prevention and immunotherapy by releasing the checkpoints on innate immune sensors. During the initial funding period, we have uncovered driver oncogenes that disable the STING pathway and promote immune tolerance, we have engineered the first-generation nanoparticles to improve the intracellular delivery of STING agonists, we have streamlined our single-cell immune analysis pipelines to render intra-lesional immune landscape as a function of time. Recently, we discovered a new pathway that suppresses HNC initiation through IFN-I activation. This renewal project will parlay our previous accomplishments and our recent discovery into a cohesive program that addresses the mechanisms of HNC resistance to STING stimulation and optimizes the engineering of a new generation of nanoparticles for innate immune priming in hosts insensitive to free STING agonists. To support this goal, we have established comprehensive modeling for HNC initiation and response plasticity to STING stimulation, including carcinogen-induced models, implantable models, and genetically engineered models. Resistance to STING stimulation disqualifies a spectrum of cold cancer priming strategies. This renewal project will uncover a pivotal molecular mechanism underpinning the fitness of innate immune sensors and optimize robust nanotechnology overcoming cancer resistance in individuals insensitive to STING stimulation.