Common Cancers Evade Detection by Silencing Parts of Immune System Cells, Study Finds
Immunotherapy for ovarian, breast, and colorectal cancer has so far had limited success, primarily because the immune system often can’t destroy the cancer cells. According to a report published in Oncotarget, researchers at Johns Hopkins have identified genes that have been repressed through so-called epigenetic changes—modifications that alter the way genes function without changing their DNA sequence—which help the cells to evade the immune system. The researchers were able to reverse these epigenetic changes with the use of an FDA-approved drug, forcing the cancer cells out of hiding and potentially making them better targets for the same immunotherapy that in the past may have failed.
“Chemotherapy often works, but in most cases, it eventually stops working,” said study author Nita Ahuja, MD, Associate Professor of Surgery, Oncology and Urology at the Johns Hopkins University School of Medicine. “What if we could get the immune system itself to fight the tumors and keep the cancer in check forever? That is the ultimate goal, and this gene panel may get us closer.”
Study Details
The researchers treated 63 cancer cell lines (26 breast, 14 colorectal, and 23 ovarian) with low-dose azacitidine (Vidaza), a DNA methyltransferase inhibitor that is FDA-approved for myelodysplastic syndrome. They identified a panel of 80 biologic pathways commonly increased in expression by azacitidine in all three cancers, finding that 16 of them (20%) are related to the immune system. These pathways appeared to be downregulated in the cancer cells, allowing for evasion. After treatment with azacitidine, the epigenetic changes were reversed, rendering the cancer cells unable to evade the immune system any longer.
The researchers found that these immune system pathways were suppressed in a large number of primary tumors—roughly 50% of ovarian cancers studied, 40% of colorectal cancers, and 30% of breast cancers. The findings may be applicable to other cancer types such as lung cancer or melanoma, they said.
After looking in cell lines, the Johns Hopkins team extended their work to human tumor samples. Again they found evidence that these immune system pathways are turned down in some patients and, that these immune genes can be turned back up in a small number of patients with breast and colorectal cancer who had been treated with epigenetic therapies.
Opening the Door for Immunotherapy
“Most of us haven’t thought of these common cancers as being immune-driven,” said Dr. Ahuja. “We haven’t held out much hope for immune therapy to work in them because before you can enter cancer cells to knock them down, you have to be able to get inside. They were locked and now we may have identified a key.”
The hope is that clinicians could eventually pinpoint which patients with these common cancers would benefit from a dose of azacitidine followed by an immunotherapy that stimulates the immune system to attack cancer cells.
“This would tell us which patients’ tumors are hiding from the immune system and will allow us to use all of our tools to flush that cancer out,” she said.
Dr. Ahuja and Cynthia Zahnow, PhD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, are the corresponding authors for the Oncotarget study.
The study was supported by grants from the National Institutes of Health’s National Cancer Institute and others. Drs. Ahuja and Zahnow are consultants for Celgene.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
