The tumor suppressor PD-1, which serves as shut-off switch to prevent damaged T-cells from continuing to develop and proliferate, is frequently missing in crucial genes of patients with T-cell lymphomas, a study reports.
The study “PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis,” published in the journal Nature, suggests that treatments that reverse the loss of PD-1 could help these patients by restoring its ability to reduce oncogenic signaling.
T-cell non-Hodgkin lymphomas are a diverse group of highly aggressive tumors. They appear to develop from peripheral T-cells, immune system cells responsible for keeping cancer cells at bay.
The genome of these T-cells can often undergo mutations of specific genes that are involved in T-cell receptor (TCR) signaling. These mutations are thought to activate genes called oncogenes, which are responsible for cell proliferation and survival. But when these genes go into overdrive, T-cells proliferate uncontrolled, and cancer results.
Another set of genes, called tumor suppressor genes, work to counteract the activities of oncogenes. But it is unclear whether T-cells contain tumor suppressors that are able to work against TCR pathways in proliferation and survival.
Researchers induced oncogenic TCR signaling in T-cells of a mouse model of human T-cell lymphoma, which led to a robust expansion of T-cells in the mice.
They found that this expansion did not last long, and was actually counteracted by mechanisms within the cell. Further genome-wide analysis of these T-cells showed that a gene called PDCD1, which codes for the PD-1 protein, was the master regulator in countering oncogenic signaling in these cells. This, the researchers reported, shows that PD-1 functions as a shut-off switch for tumor growth.
The team then looked at the prevalence of deletions of PDCD1 in human T-cell lymphomas using genetic data from 150 patients, and found deletions are prevalent in more than 30 percent of genes for this master regulator.
“In individual groups more than 30 % of the patients exhibited changes in the regions of the genome which interfered with the production of PD-1. This has disastrous consequences in the tumor — PD-1 no longer functions as an ’emergency shut-off’ for them,” Tim Wartewig, the study’s lead author, said in a press release. “The diseased T-cells can reproduce uncontrollably.”
PD-1 exerts its effects by recruiting other tumor suppressors, including a protein called PTEN, which reduce oncogenic signaling. But when PDCD1 is lost in these T-cells, oncogenic signaling goes unchecked, leading to the development of highly aggressive lymphomas in the mouse models.
“These patients could be helped by medications that reverse the loss of PD-1 signaling and thereby destroy the tumor cells. This type of medication already exists for other forms of cancer,” said Dr. Jürgen Ruland, principal investigator at the TUM Central Institute for Translational Cancer Research (TranslaTUM). “In our opinion, use with T cell Non-Hodgkin’s lymphoma should also be considered.”