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Reviving the Immune Response in Pancreatic Cancer

Thursday, June 01, 2023
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                             Loretah Chibaya, PhD                                                     Marcus Ruscetti, PhD

Late detection, aggressive growth, and a sleepy immune system make pancreatic cancer a formidable opponent. Its refusal to bend to even the most toxic therapies made it untouchable even when immunotherapy—known for its ability to ignite immune responses—revolutionized the field. 

No wonder the five-year survival rate for metastatic pancreatic cancer is just 10%-11% and it ranks as the third leading cause of cancer-related deaths!

The reason it can so relentlessly assault lies partly in the power of its tumor microenvironment (or TME)—a community of blood vessels, immune cells and supportive tissues. The TME surrounds the tumors, releasing factors that shield them from the immune system, helping them thrive. 

We are in dire need of a fresh way to disarm pancreatic cancer. Luckily, Marcus Ruscetti, PhD, and his team are executing an ingenious plan to give the immune system just the jolt it needs.

Taking on the challenge

While a post-doctoral fellow, Dr. Ruscetti, and his colleagues were able to leverage the immune system in pancreatic cancer by targeting the KRAS mutation—a culprit in >90% of pancreatic cancers and 20%-40% of lung cancers. To initiate the desired immune response, they used an investigational drug combination consisting of the MEK inhibitor, trametinib and the CDK4/6 inhibitor, palbociclib—or T/P. This drug activates an immune response through a process known as a senescent-associated secretory phenotype, or SASP, in which senescent cells release factors that promote inflammation.

T/P rallied an innate immune response in lung, but not pancreatic cancer. It did so by summoning natural killer (NK) cells that act as one of the body’s first lines of attack against cancerous cells. 

But, why aren’t NK cells activated after T/P therapy in pancreatic cancer?

As he puzzled over this question, Dr. Ruscetti transitioned to a new position as an assistant professor at UMass Chan and assembled his lab. Ready to tackle the problem, his talented post-doctoral fellow, Loretah Chibaya, PhD, led the team on a clever study that recently appeared in Nature Cancer.

“Because similar mutations drive both lung and pancreatic cancer, I thought the disparate immune responses probably stemmed from differences in their TMEs, rather than in the tumors themselves,” says Dr. Chibaya. 

To test this hypothesis, the team used a preclinical mouse cancer model and grew pancreas ductal adenocarcinoma (PDAC) tumors in the lung and lung adenocarcinoma (LUAD) in the pancreas. This manipulation pitted tumor type against TME

Next, they treated the tumors with T/P and waited.  

The results proved Dr. Chibaya was correct! 

Following therapy-induced senescence, NK cell immune responses were activated for tumors implanted in the lung but absent for tumors grown in the pancreas. Therefore, something in the TME of pancreatic tumors must be blocking NK cell stimulation.

Digging deeper

They used RNA sequencing to determine which genes were expressed in the tumor tissue and in what quantities. They found that targets of the gene enhancer of zeste homolog 2 (or EZH2) were expressed differently in tumors grown in the pancreas as compared to the lungs. The team further showed that EZH2 suppressed SASP—the program that churns out inflammatory molecules. Perhaps it is the high levels of EZH2 that prevent NK cell surveillance in pancreatic cancer.

To test this theory, Dr. Chibaya genetically knocked down EZH2 in the pancreatic tumor cells, implanted them in mice and treated them with T/P. 

“Our results showed something we had never seen before in our pancreatic cancer models. Many of the mice were cured! The tumors didn’t return, even when mice were taken off the drug,” says Dr. Ruscetti.

The ultimate goal is to treat humans which will require less invasive means than gene manipulation. Therefore, the team repeated the experiment using an EZH2 inhibitor. The news was encouraging—as with genetic knockdown, the drug rustled up NK cells to fight the tumor.

A translational spin

While more work must be done before pancreatic cancer patients can be tested with a combination of T/P and an EZH2 inhibitor, the team collaborated with physicians at UMass Memorial to take an early peek at whether EZH2 plays a role in human pancreatic cancer. The group examined pancreatic tumor tissue from 34 patients, finding that those with worse survival statistics had higher expression of EZH2 in their tumors and fewer T and NK cells compared to pancreatic cancer patients with better outcomes.

“UMass Chan is becoming a top place to do pancreatic cancer research because we’re accruing a critical mass of clinical and basic pancreatic cancer researchers working together in a collegial environment,” says Dr. Ruscetti.

Collaborations between clinicians and basic researchers like Drs. Ruscetti and Chibaya bridge a crucial gap, bringing us closer to the day when pancreatic cancer will no longer have a say.

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