Sylvester Researchers Discover a Possible Pathway for Immune Therapy in Pancreatic Cancer

Immune therapy has not worked well in pancreatic cancer because of the cancer’s inherent immune resistance. Sylvester Comprehensive Cancer Center scientists have discovered a way to outsmart the deadly cancer’s ability to prevent immune checkpoint inhibitor therapy from killing pancreatic cancer cells.

“To be able to harness the treatment potential of immune checkpoint inhibitor therapy for pancreatic cancer patients by using a metabolic inhibitor is of huge significance in pancreatic cancer,” said study author Ashok K. Saluja, Ph.D., professor and vice chair for research in the Department of Surgery at the University of Miami Miller School of Medicine.

The Sylvester team’s results were published October 15 in the Journal of Clinical Investigation.

“Immune therapy has worked very well for a number of cancers and is one of today’s most sought-after therapy options because it provides a more lasting anti-cancer effect with lesser side effects,” said study author Sulagna Banerjee, Ph.D., associate professor of surgery. “Pancreatic tumors, however, are notoriously immune resistant, partly because there is a lot of heterogeneity within the tumor but mostly because of the dense stroma that acts as a barrier preventing cytotoxic immune cells to infiltrate the tumor and eradicate the cells.”

Dr. Banerjee and colleagues conduct research on pancreatic tumors’ metabolic vulnerabilities, attempting to exploit different metabolic pathways that are specific to pancreatic cancer. They then determine if targeting the pathway would make the tumor more susceptible to various therapies.

In this case, they targeted a long-ignored pancreatic cancer metabolic pathway, called the hexosamine biosynthesis.

In essence, they found that targeting glutamine in the hexosamine biosynthesis metabolic pathway in pancreatic cancer prevents synthesis of the tumor’s stroma matrix. This weakens the wall-like stroma and allows immune cells to infiltrate. The tumor then becomes susceptible to immune therapy.

“The key finding is that by inhibiting this metabolic pathway inside the tumor cells, we were able to program the tumor microenvironment to let in cytotoxic immune cells. The inhibitor also inhibits cancer stem cells,” Dr. Banerjee said. “We published a study earlier this year showing that the addition of a specific sugar molecule on the Sox2 gene contributes to the tumor recurrence properties in pancreatic adenocarcinoma. It was a prequel to this study, which shows inhibition of hexosamine biosynthesis prevents addition of this sugar molecule on Sox2. Thus, it also prevents tumor recurrence.”

This double-edged approach is going to be vital in developing better treatments for pancreatic cancer, according to Dr. Banerjee.

Targeting metabolic pathways in tumors has gained momentum and importance in recent years, with various levels of success in pancreatic cancer. The most studied, according to Dr. Banerjee, is the indoleamine-2,3-dioxygenase 1 (IDO) inhibitor, which is over-expressed in a number of cancers. Inhibiting it sensitizes tumors to immune therapy, but its use in pancreatic cancer has not panned out because of tumor relapse.

“To the best of my knowledge, this is the first time anyone has shown sensitization to immune therapy using a metabolic inhibitor in pancreatic cancer,” said Dr. Banerjee.

The implications of this research could be a game-changer for pancreatic cancer patients, 93% of whom die within five years of receiving the diagnosis.

“Even in 2019, when other cancers show an improvement in their survival statistics, five-year survival for pancreatic cancer remains in single digits. There is a desperate need for novel therapies that can change this scenario,” said Dr. Saluja, who is also associate director for research innovation.

Drs. Banerjee and Saluja plan to conduct more research looking into the effect of inhibiting hexosamine biosynthesis in immune cells.

“We want to better understand if this pathway is active only in the tumor or has a role in determining the functionality of the immune cells,” Dr. Banerjee said. “Right now, we are preventing use of glutamine by this pathway. Glutamine may have other roles to play, as well. One of the approaches we are pursuing is to identify if any other nodes on this pathway can be targeted and, if so, will the effect be better or worse?”

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