Reprogramming tumor microenvironment could improve prospects for treatment of pancreatic cancer

Pancreatic cancer presents a formidable challenge due to its aggressive nature and resistance to treatment. A key factor contributing to its tenacity is the tumor microenvironment, a dense tissue surrounding the tumor that acts as a protective barrier and dampens the immune response. This environment, comprising supportive cells, blood vessels, and immune cells, constitutes up to 90% of the tumor mass.

Among the tumor-supporting cells, cancer-associated fibroblasts (CAFs) are particularly significant. These mutated connective tissue cells stimulate tumor growth and spread by creating a scar-like tissue structure and suppressing the immune system, rendering many immunotherapies ineffective against pancreatic cancer.

Researchers at the Karlsruhe Institute of Technology (KIT) have uncovered a molecular mechanism that governs the tumor-supporting environment. Central to this mechanism is CD44, a molecule that influences the behavior of CAFs. Their study, published in Cell Death & Disease, reveals that CD44 amplifies crucial signals that activate these fibroblasts.

By inactivating CD44 in both mouse models and human cells, the researchers observed a marked change in the fibroblasts' behavior. They produced less extracellular matrix, released fewer cytokines, and lost their capacity to impede the immune system. Consequently, immune cells could target the tumor cells more effectively, leading to a significant reduction in tumor size in the mouse models.

The implications of this discovery are promising. Inactivating CD44 in pancreatic cancer-associated fibroblasts alters their fibrotic and immunosuppressive functions, enhancing the immune attack and reducing tumor size. This finding aligns with a therapeutic approach pursued at KIT, where blocking certain CD44 variants on cancer cells has shown potential in slowing pancreatic cancer progression.

A peptide directed at CD44v6, a specific variant, has already undergone clinical testing. The researchers' current results suggest that targeting CD44 in the tumor-supporting tissue could also offer therapeutic benefits. However, further research is necessary to translate these findings into a clinical application. The study involved researchers from TRON at the University Medical Center of Johannes Gutenberg University Mainz and the University of Freiburg, underscoring the collaborative nature of this significant scientific endeavor.