Researchers at The University of Texas MD Anderson Cancer Center have identified that the tumor suppressor BATF2 can be silenced by factors within the tumor microenvironment. This silencing has been observed to lead to a reduced immune response in five preclinical models of head and neck cancer. The findings were published in Nature Communications, with the study led by Yu Leo Lei, D.D.S., Ph.D., associate professor of Head and Neck Surgery, Cancer Biology, and Translational Molecular Pathology.
BATF2 and Immune Function
BATF2 functions as a tumor suppressor involved in regulating immune responses, contributing to anti-tumor immune surveillance. It is expressed by epithelial and myeloid cells and can directly activate the STING pathway. The STING pathway is known to play a role in innate immunity by initiating Type-I interferon (IFN-I) production, which drives T cell-mediated protection against tumors. The study found a correlation between BATF2 levels and IFN-I and Th1 immune signatures in patient tumors, indicating a relationship between higher BATF2 levels and the recruitment of immune cells to tumors.
Glutamine's Role in BATF2 Silencing
Many cancers exhibit resistance to treatments targeting the STING pathway. Research has indicated that epigenetic changes, which modify gene activity without altering DNA sequences, can arise from metabolic signals in the tumor microenvironment. Specifically, an inverse correlation was observed between BATF2 and IFN-I genes and genes associated with glutamine metabolism. Glutamine is an amino acid utilized by cells for growth.
The study showed that a glutamine-rich environment can silence the BATF2 gene. This silencing was linked to a weakened immune response, decreased IFN-I production, and increased oxygen consumption, which may facilitate the growth of cancer cells and evade immune detection. Conversely, the use of drugs that inhibit glutamine metabolism restored IFN-I production and increased the sensitivity of cancer cells to STING pathway-targeting drugs, leading to an improved antitumor response.
Preclinical Implications
While these results are based on preclinical models and require further investigation, the findings suggest that regulating glutamine levels to enhance BATF2 expression in the tumor microenvironment could potentially improve the immune response in patients with head and neck cancers, particularly those resistant to STING pathway treatments.