Oral Cancer Cells Use Fat as Fuel to Escape from Immunity

New study identifies the role of metabolic comorbidities such as obesity in contributing to the immunogenicity of oral cancer through the immune pathway STING-IFN-I.

Saturated fatty acids present in the microenvironment of oral cancer cells may dampen the tumor response to STING stimulation. Destabilizing STING in epithelial cell-derived cancer cells, such as head and neck squamous cell carcinomas (HNSCCs) can promote immune escape.

A research team from the University of Michigan Rogel Cancer Center and School of Dentistry have identified a mechanism in mice for how obesity affects some oral cancers’ ability to escape from the immune system.

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‘Obesity helps oral cancer cells to establish a microenvironment deprived of immune pathways with anti-tumour immunity and promote its growth.’

Their study published in Cell Reports found that obesity helps to establish a type of tumor microenvironment that promotes tumor progression. How exactly this happens lies in the relationship between the saturated fatty acids, the STING-type-I interferon pathway, and NLRC3 ().

Obesity Linked with Immune Evasion of Oral Cancers in Mice

Generally, researchers tend to think about the increased risks for gastrointestinal tumors, breast cancer, pancreatic cancer, and ovarian cancer when it comes to obesity. But its role in oral cancer remains unknown. Multiple studies involving millions of individuals from several continents revealed a previously underappreciated link between obesity and oral cancer risks ().

Myeloid cells in obese mice were insensitive to STING agonists and were more suppressive of T cell activation compared to the myeloid cells from leans hosts. This feature drove the loss of immune subsets that were crucial for anti-tumor immunity in the tumor microenvironment.

They found that saturated fatty acids can block the STING pathway, which is induced by cytosolic DNA and promotes antigen-presenting cell maturation, by inducing a protein called NLRC3. This is the first study establishing a mechanistic link between obesity with oral cancer immune escape ().

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Obesity is a common comorbidity in cancer patients. Two recent studies found that oral cancer patients who were on statins—medicines that lower cholesterol—showed improved overall and cancer-specific survival.

This study again establishes a mechanistic link for those observations and highlights the potential of targeting fatty acids metabolism in remodeling the host anti-tumor immune response. Next, researchers will explore how obesity regulates other immune-activating pathways and identify novel intervention targets for better oral cancer prevention in high-risk individuals.

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References:

HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING - (https://www.jci.org/articles/view/129497)
Saturated fatty acids dampen the immunogenicity of cancer by suppressing STING - (https://doi.org/10.1016/j.celrep.2023.112303)
Statin use associated with improved overall and cancer specific survival in patients with head and neck cancer - (https://www.sciencedirect.com/science/article/abs/pii/S1368837519300302?via%3Dihub)

Source-Eurekalert

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