WHY Is Pancreatic Cancer RESISTANT to Immunotherapy, and Can This Resistance Be Broken?

Pancreatic ductal adenocarcinoma (conventional pancreatic cancer)still has 5-year survival around % 5 to % 7, and melanoma and lung cancer immunotherapies have not prolonged pancreatic cancer survival. Many oncology professionals investigate why. At November 2019's Maryland 34th Society for Immunotherapy of Cancer meeting (SITC 2019), studies suggested immunosuppression in the tumor microenvironment explains limited effectiveness; 2 noteworthy studies were presented.

The First Studyshowed an immunosuppressive peptide reducing active T-cell proliferation and altering maturation, suppressing theimmune system , vasoactive intestinal peptide (VIP), occurs in exceptionally large amounts in pancreatic cancers.

Emory University's Winship Cancer Institute postdoctoral researcher Sruthi Ravindranathan in Atlanta said: “We examined The Cancer Genome Atlas for VIP levels in human solid tumors and found them highest in pancreatic cancer.” Researchers then examined 10 patient blood samples and found levels far above healthy individuals.

Why Is VIP High? Does It Affect Tumor Growth or Response? Does It Suppress Immunity?

Researchers used mouse models to test agents binding VIP receptors and blocking function, 2 antagonists (ANT-00 and ANT-08), combined with anti-PD-1 immunotherapy treatment, such as nivolumab or pembrolizumab. They used pancreatic cancer mouse models to test the combination’s in vivo effectiveness on tumor growth.

Mice were split into 3 groups: VIP antagonist, anti-PD-1 immunotherapy, or both. Combination treatment best reduced tumors.

Combination-treated mice had substantially better median survival and increased tumor infiltration by CD4 + and CD8 + T cells . Following these promising preliminary results, the team prepared human trials.

The Second Studyfocused on a molecule secreted by regulatory B cells, IL-35 , examining the role of B-cell-secreted cytokines in immunosuppression in pancreatic cancer.

Dr. Yuliya Pylayeva-Gupta, Lineberger Cancer Center, University of North Carolina at Chapel Hill, said: “We initially found this cytokine expressed in patient samples and pancreatic cancer mouse models,” and added: “B lymphocytes infiltrated tumors in mice and humans. Normally they circulate in blood and remain in lymphoid tissues.” She added.

- Related topic: What are B-cell lymphocytes? Functions and antibody production

IL-35 previously suppressed immune responses in autoimmune diseases, where immunity mistakenly attacks healthy cells, but had not been extensively studied in pancreatic cancer.

To investigate IL-35 in pancreatic cancer, researchers used 2 main strategies, first creating a mouse model whose B cells could not produce IL-35.

“When we deleted IL-35 in B lymphocytes, tumors did not grow. Blocking IL-35 attracts cytotoxic, cell-killing T cells far more frequently. We see an immune response and further tumor shrinkage,” Dr. Pylayeva-Gupta says.

They also combined anti-PD-1 immunotherapy with an IL-35 inhibitor to assess sensitization of pancreatic mouse tumors.

One reason immunotherapy may fail is that even pancreatic tumors positive for PD-L1 often lack cytotoxic T-cell infiltration. Researchers eliminated IL-35 to permit infiltration, then gave anti-PD-1 immunotherapy to stimulate responses.

The team plans further development of an IL-35 blocker, not yet ready for human use.

Dr. Pylayeva-Gupta says: “We want to learn how these immunosuppressive B cells arise in cancers and produce these cytokines. Perhaps this applies to other cancers—we are investigating.”

In conclusion, we increasingly understand cancer biology to be one of the universe's most complex subjects . Growing knowledge opens new promising treatments. Melanoma, once exceptionally resistant, became controllable with immunotherapy. These two studies and similar work offer hope for effective pancreatic treatments.