SWCRF-funded research team at Johns Hopkins identifies genes that predict tumors that “hide” from the immune system.

The Samuel Waxman Cancer Research Foundation congratulates its team of funded researchers at Johns Hopkins UniversityStephen Baylin, M.D., Robert Casero, Ph.D., and Cynthia Zahnow, Ph.D., who, along with other researchers at Johns Hopkins, published a report in the journal Oncotarget detailing their discovery of genes that may predict tumors that evade detection from the immune system. The team’s research has produced a clinical trial in lung cancer that may lead to a new class of treatment.

Immune therapy for ovarian, breast and colorectal cancer - treatments that encourage the immune system to attack cancer cells as foreign invaders - has so far had limited success, primarily because the immune system often can't destroy the cancer cells.

In a report published online Feb. 16 in the journal Oncotarget, the Johns Hopkins team says it has identified genes that have been repressed through 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 immune therapy that in the past may have failed.

The researchers treated 63 cancer cell lines (including breast, colorectal and ovarian) with low-dose 5-azacitidine (AZA), an FDA-approved drug for myelodysplastic syndrome, that reverses epigenetic changes by stripping off the methyl group that silences the gene. They identified a panel of 80 biological pathways commonly increased in expression by AZA in all three cancers, finding that 20 percent of them are related to the immune system. These pathways appeared to be dialed down in the cancer cells, allowing for evasion. After treatment with AZA, 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 . After looking in cell lines, the Johns Hopkins team extended their work to human tumor samples. They again 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

The hope is that clinicians could eventually pinpoint which patients with these common cancers would benefit from a dose of AZA followed by an immune therapy that stimulates the immune system to attack cancer cells.

The Johns Hopkins team has put the panel into use in a lung cancer trial. Six patients were treated first with epigenetic therapy followed by immune therapy. Though the sample is small and time has been short, four of the patients have had their cancer suppressed for many months. 

The Oncotarget paper can be viewed here.