Immunotherapy Enhances Attack on Pancreatic Cancer Tumors

Macrophages can penetrate the surrounding walls that protect pancreatic cancer from chemotherapy.

Macrophages can penetrate the surrounding walls that protect pancreatic cancer from chemotherapy with the help from immunotherapy, a recent study found.

Macrophages are immune cell subsets most commonly associated with helping tumor growth.

However, the preclinical study published in Cancer Discovery found the necessary steps needed to redirect macrophages to attack the microenvironment.

"We've unraveled some of the complex, bidirectional messaging between a tumor and its microenvironment,” lead study author Gregory L. Beatty, MD, PhD. “We've learned how antibodies that target a cell surface molecule called CD40 work with the immune system to tear back that wall.

“Additionally, our findings identify a novel role for CD40 antibodies--as a 'lead-in' therapy to enhance the efficacy of chemotherapy and possibly other biological treatments for pancreatic cancer.”

During the study, researchers were able to identify in a mouse model the role played by factors such as chemokine ligand 2 (CCL2) and interferon gamma (IFN-?), which the immune system releases after treatment with CD40 antibodies to redirect macrophages.

CCL2 is a requirement for macrophages to infiltrate tumors, while IFN-y is a requirement to re-educate macrophages to release key enzyme metalloproteinases, which are responsible for degrading the microenvironment that protects the tumors from chemotherapy. This is what leads to fibrosis degradation.

Researchers also found that after CD40 treatment, the fibrotic scaffold that surrounds the tumors stayed degraded for up to a week. This suggests that chemotherapy treatment will have the most effective results during this time period.

When the mice were treated with gemcitabine a mere 2 days after getting CD40 antibodies, they had a low tolerance to the chemotherapy and had significant weight loss with 30% mortality.

In comparison, mice administered gemcitabine 5 days after the antibodies were able to tolerate the chemo, while also producing clinical activity marked by tumor reduction and cell death.

"Together, we believe that this data supports further investigation of therapeutics that redirect monocytes and macrophages, rather than depleting them,” Beatty said. “Macrophages can be very potent killers of cancer. Since keeping them out of tumors is a challenge, why not harness their recruitment? This may be the Achilles heel of pancreatic cancer. Now that we better understand this biology, we are hopeful that our findings will spark further clinical interest and a path forward to test this treatment approach in patients."

Back in 2011, a study was published that documented CD40’s ability to re-educate monocytes and macrophages into the tissue and blood in order to break down the tumor microenvironment in both mice and humans.

It came as a surprise when the study showed CD40 antibodies stimulate the macrophages in order to attack pancreatic cancer by activating T-cells. However, the biology behind this remained unclear and there was no role detection for T-cells.