Loss of function mutations to MLL3—an important but poorly understood tumor suppressor gene also known as KMT2C—occur frequently in various types of cancer including breast, lung, colorectal and bladder cancers. MLL3 mutations are thought to help tumors resist immune attack, but the underlying molecular mechanisms are not known.

Using a powerful mammary stem cell-based tumor model, Gregoire Lauvau, Ph.D., Wenjun Guo, Ph.D., and colleagues at Einstein and Montefiore discovered that the effects of MLL3 loss are driven by HIF1alpha, a transcription factor activated under the low-oxygen conditions commonly found in tumors. HIF1alpha-mediated MLL3 loss accelerates tumor onset by promoting tumors to recruit a subset of regulatory lymphocytes, known as Foxp3+ regulatory T (Treg) cells, which further differentiate into highly immune-suppressive Tregs in early tumor lesions. The researchers proposed and successfully tested a potentially promising therapeutic strategy: target the cell-surface receptors ICOS and GITR, which are mainly expressed by the immune-suppressive Tregs in the tumors. The findings were published online on July 31 in the journal Immunity.

Dr. Lauvau is professor of microbiology & immunology and the Sylvia and Robert S. Olnick Faculty Scholar in Cancer Research at Einstein and a member of the National Cancer Institute–designated Montefiore Einstein Comprehensive Cancer Center (MECCC) Marilyn and Stanley M. Katz Institute for Immunotherapy for Cancer and Inflammatory Disorders, the Cancer Therapeutics research program and the Cancer Dormancy Institute. Dr. Guo is professor of cell biology and a member of the Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine at Einstein, and a member of the Cancer Dormancy Institute and the Marilyn and Stanley M. Katz Institute for Immunotherapy for Cancer and Inflammatory Disorders at the MECCC.