Head and neck squamous cell carcinoma (HNSCC) develops in the mucous membranes of the mouth, nose, and throat. It is an aggressive life-threatening disease associated with high mortality rates, and accounts for more than 90% of the cancers of the head and neck.
PD1 blockade-based combination therapy has been approved as a first-line treatment for HNSCC. However, the response rate remains relatively low, and patients with HNSCC eventually relapse. Now scientists at the UCLA Jonsson Comprehensive Cancer Center and UCLA School of Dentistry have revealed a potential new combination therapy to treat advanced head and neck squamous cell carcinoma. Using a mouse model, researchers found that using an anti-PD1 immunotherapy drug in combination with PTC209, an inhibitor that targets the protein BMI1, successfully stopped the growth and spread of the cancer, prevented reoccurrences, and eliminated cancer stem cells.
Their findings, “BMI1 Inhibition Eliminates Residual Cancer Stem Cells after PD1 Blockade and Activates Antitumor Immunity to Prevent Metastasis and Relapse,” is published in Cell Stem Cell.
PD1 blockade combined with chemotherapy has been approved for recurrent or metastatic head and neck cancer. However, response rates remain low and response duration is suggesting that this type of cancer might be resistant to PD1 blockade.
The researchers sought to overcome the resistance and had been studying the role of cancer stem cells and the protein BMI1. BMI1, a polycomb group (PcG) protein, plays a critical role in epigenetic regulation of cell differentiation and proliferation, and cancer stem cell self-renewal.
The researchers used a mouse model of HNSCC that mimicked human cancer development and metastasis, allowing them to perform lineage tracing of BMI1-positive cancer stem cells in an undisturbed tumor immune microenvironment. Then they tested whether BMI1 cancer stem cells could be eliminated by PD1 blockade-based combination therapy using both pharmacological and genetic inhibition of BMI1.
“Here, we show that the combination treatment of anti-PD1 and cisplatin enriched BMI1+ CSCs in HNSCC while inhibiting HNSCC growth. In contrast, the pharmacological and genetic inhibition of BMI1 eliminated BMI1+ CSCs and enabled PD1 blockade therapy, resulting in the inhibition of metastatic HNSCC and prevention of HNSCC relapses,” the researchers wrote.
BMI1 inhibition induced tumor cell-intrinsic immune responses by recruiting and activating CD8+ T cells along with eliminating BMI1 and cancer stem cells.
This is the first preclinical study to provide evidence that targeting BMI1 proteins enhances immunotherapy and eliminates cancer stem cells by activating antitumor immunity. This discovery holds promise for those with advanced head and neck cancers who are treated with PD1 blockade, but later become resistant to therapy.