Researchers are looking for ways to enhance the antitumor response. Now, researchers at Weill Cornell Medicine and Albert Einstein College of Medicine, report they have discovered tumors can use an enzyme called ART1 to thwart antitumor immune cells.
Their findings are published in the journal Science Translational Medicine in a paper titled, “Expression of the mono-ADP-ribosyltransferase ART1 by tumor cells mediates immune resistance in non–small cell lung cancer.”
The researchers observed that ART1, when expressed in tumor cells, can modify a receptor on tumor-fighting immune cells in a way that triggers the death of these immune cells. In animal models of cancer, blocking ART1 increased the presence of the tumor-fighting immune cells within tumors and slowed or stopped tumor growth.
“Most patients with non–small cell lung cancer (NSCLC) do not achieve durable clinical responses from immune checkpoint inhibitors, suggesting the existence of additional resistance mechanisms. Nicotinamide adenine dinucleotide (NAD)—induced cell death (NICD) of P2X7 receptor (P2X7R)—expressing T cells regulates immune homeostasis in inflamed tissues. This process is mediated by mono–adenosine 5′-diphosphate (ADP)–ribosyltransferases (ARTs). We found an association between membranous expression of ART1 on tumor cells and reduced CD8 T cell infiltration. Specifically, we observed a reduction in the P2X7R+ CD8 T cell subset in human lung adenocarcinomas.”
“These findings should allow us to add to our medicinal toolkit for enhancing the antitumor immune response, to benefit cancer patients,” said study co-corresponding author Timothy McGraw, PhD, professor of biochemistry and of biochemistry in cardiothoracic surgery and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
“Our main focus in this study was lung cancer, but there is evidence that this immune-evasion mechanism is at work also in other kinds of cancer,” explained co-corresponding author Sandra Demaria, PhD, professor of radiation oncology and of pathology and laboratory medicine and a member of the Meyer Cancer Center at Weill Cornell Medicine.
“This is an excellent example of how translational science should work. We first found ART1 expressed in the tumors of patients with lung cancer. In the lab, we discovered that ART1 helps to block the antitumor immune response, specifically by inducing death of antitumor T cells. We then developed a therapeutic antibody that blocks the function of ART1, allows the immune system to fight the cancer and ultimately prolongs survival in tumor models,” said senior author Brendon Stiles, MD, formerly of Weill Cornell Medicine and now chief of the division of thoracic surgery and surgical oncology and associate director of surgical services at Montefiore Einstein Cancer Center and professor of cardiovascular and thoracic surgery at Albert Einstein College of Medicine. “Hopefully, we can very soon take that antibody back to treat our patients with cancer.”
Further experiments in mice with NSCLC and melanoma tumors revealed that reducing ART1 led to a greater presence within tumors of CD8 T cells, the immune system’s most powerful weapon against cancers.
