Scientists unlock the potential of Myeloid cells to cure pancreatic cancer

The results were published in the journal Science Immunology, and the lead author was Dr. Max M. Wattenberg, a cancer biologist at the Perelman School of Medicine.

How the combination therapy works

The two treatments are a drug called β-glucan, which activates a receptor called dectin-1 on the myeloid cells, and an antibody that binds to another receptor called CD40 on the same cells. By co-activating these receptors, the researchers were able to turn the myeloid cells into tumor killers and boost the activity of the T cells.

“By co-targeting myeloid activation molecules, we leveraged the myeloid compartment as a therapeutic vulnerability,” Wattenberg said. “Myeloid cells in solid tumors expressed activation receptors including the pattern recognition receptor dectin-1 and the TNF receptor superfamily member CD40. 

In mouse models of checkpoint inhibitor-resistant pancreatic cancer, co-activation of dectin-1, via systemic β-glucan therapy, and CD40, with agonist antibody treatment, eradicated established tumors.”

Targeting both myeloid cell activating receptors—CD40 and dectin-1—created a potent myeloid-based response against tumors, overcoming the naturally immunosuppressive signals of the tumor microenvironment.

Why T cells are still important

The researchers found that the antitumor activity of the combination therapy was dependent on the presence of T cells but not on their ability to kill the cancer cells directly or block their escape mechanisms.

“Antitumor activity was dependent on … T cells but did not require classical T cell–mediated cytotoxicity or blockade of checkpoint molecules,” Wattenberg wrote. “Rather, targeting CD40 drove T cell–mediated interferon-gamma signaling, which converged with dectin-1 activation to program distinct macrophage subsets to facilitate tumor responses.”

To be clear, the findings demonstrate that the antitumor activity of dectin-1/CD40 activation required T cells but was completely independent of T cell cytotoxicity and immune checkpoint pathways.

Wattenberg and colleagues emphasize that antitumor activity also requires interferon-gamma and intra-tumoral macrophages. 

Interferon-gamma is a molecule that helps activate the immune system, and macrophages are a type of myeloid cell that can engulf and destroy foreign invaders.

A new immunotherapy paradigm

The findings demonstrate that targeting myeloid cell activation pathways can generate strong antitumor immune responses against tumors resistant to conventional immunotherapy.

“These findings define a previously-undescribed immunotherapy paradigm via co-activation of complementary myeloid signaling pathways,” concluded Wattenberg, noting that a clinical trial studying a combination immunotherapy treatment for patients with pancreatic ductal adenocarcinoma is underway.

The researchers hope their findings will pave the way for new clinical trials in humans and offer hope for pancreatic cancer patients who have not benefited from existing immunotherapies. They also believe that their strategy could be applied to other types of cancer that are resistant to T cell-based immunotherapy.

Myeloid cells

Myeloid cells are a diverse group of immune cells originating from the bone marrow. They include erythrocytes (red blood cells), platelets, granulocytes (such as basophils, eosinophils, and neutrophils), monocytes, and myeloid dendritic cells. 

These cells have various functions in the immune system, such as inflammation, wound healing, and antigen presentation. However, the tumor can also hijack some of them to suppress the immune response. The researchers found that activating the dectin-1 and CD40 receptors could reverse this process and make the myeloid cells fight the tumor instead.

Pancreatic ductal adenocarcinoma is the most common type of pancreatic cancer, accounting for about 95% of cases. It arises from the cells lining the pancreas’s ducts, which produce digestive enzymes and hormones. 

It is often diagnosed late when the tumor has spread to other organs. The survival rate for this type of cancer is very low, with only about 10% of patients living for five years after diagnosis. The current treatments include surgery, chemotherapy, radiation, and targeted therapy, but none of them are very effective.

Study abstract

Myeloid cells facilitate T cell immune evasion in cancer yet are pliable and have antitumor potential. Here, by cotargeting myeloid activation molecules, we leveraged the myeloid compartment as a therapeutic vulnerability in mouse models of pancreatic cancer. Myeloid cells in solid tumors expressed activation receptors including the pattern recognition receptor Dectin-1 and the TNF receptor superfamily member CD40. In mouse models of checkpoint inhibitor–resistant pancreatic cancer, coactivation of Dectin-1, via systemic β-glucan therapy, and CD40, with agonist antibody treatment, eradicated established tumors and induced immunological memory. Antitumor activity was dependent on cDC1s and T cells but did not require classical T cell–mediated cytotoxicity or blockade of checkpoint molecules. Rather, targeting CD40 drove T cell–mediated IFN-γ signaling, which converged with Dectin-1 activation to program distinct macrophage subsets to facilitate tumor responses. Thus, productive cancer immune surveillance in pancreatic tumors resistant to checkpoint inhibition can be invoked by coactivation of complementary myeloid signaling pathways.