A recent study has identified a molecule, the transcription factor HOXD13, as a driver of skin cancer growth and a mechanism through which tumors evade the immune system. Researchers at NYU Langone Health and its Perlmutter Cancer Center led the study.
Role of HOXD13 in Cancer Growth
HOXD13 is essential for the growth of blood vessels that supply melanoma tumor cells with oxygen and nutrients, a process known as angiogenesis. Transcription factors regulate the rate at which genetic instructions form proteins.
The study found that HOXD13 stimulates activity in signaling pathways, including those involving vascular endothelial growth factor (VEGF), semaphorin-3A (SEMA3A), and CD73, which increase blood supply to tumors.
Suppressing HOXD13 activity resulted in tumor shrinkage in experiments.
Immune Evasion
The researchers also observed that melanoma patients with high HOXD13 activity had lower blood levels of cytotoxic T cells, which are crucial for recognizing and killing cancer cells. The ability of T cells to infiltrate tumors was also reduced in these patients.
HOXD13 alters the tumor microenvironment to hinder immune function.
It achieves this by increasing levels of CD73, which in turn elevates adenosine. Adenosine acts as a protective shield for tumors by inhibiting T cells and preventing their entry.
When HOXD13 was deactivated, an increase in T cell infiltration into tumors was observed.
Treatment Implications
This data suggests that a combined approach targeting angiogenesis and adenosine-receptor pathways could be a promising treatment for HOXD13-driven melanoma. Separate clinical trials are currently evaluating the safety and efficacy of VEGF-receptor and adenosine-receptor inhibitor medications for melanoma and other cancers, sometimes in combination with other immunotherapies.
Plans are underway to initiate clinical investigations using a combination of VEGF and adenosine-receptor inhibitors to treat melanoma in patients with elevated HOXD13 levels.
Researchers also plan to investigate these pathways as potential targets for other cancers, including certain glioblastomas, sarcomas, and osteosarcomas, where increased HOXD13 is present.
Study Methodology
The study involved analyzing tumors from over 200 melanoma patients from the U.S., Brazil, and Mexico. Further experiments were conducted in mice and human melanoma cell lines to confirm HOXD13's role in angiogenesis and immune evasion. Inhibition tests of HOXD13, VEGF, and adenosine confirmed HOXD13's importance in cancer growth and survival.