A report published recently in the Journal of Clinical Investigation, describes how anti-angiogenesis treatment induces a microenvironment that suppresses immune systems actions that would otherwise help to eliminate a tumor. A potential gene therapy approach for getting around this resistance mechanism is also explored.
Often given in combination with traditional therapies, angiogenesis inhibitors work by restricting the growth of new blood vessels and by “normalizing” the abnormal vessels in and around a tumor that can interfere with both chemotherapy and radiation therapy. Unfortunately, as tumors rapidly develop resistance to anti-angiogenic therapy, these agents provide limited survival benefits.
“Deciphering and targeting mechanisms involved in resistance to anti-angiogenic therapy is critical to realizing the full potential of this promising cancer therapy,” commented co-senior author of the paper, Dai Fukumura (Massachusetts General Hospital, MA, USA). “Not only is this the first report investigating the role in anti-angiogenic cancer therapy of a subset of innate immune cells – Ly6Clow or non-classical monocytes – it is also the first to find an immunosuppressive function for these cells and to identify that as the key mechanism conferring resistance to anti-angiogenic therapy.”
Examining mouse models of colorectal cancer revealed that treatments blocking the vascular endothelial growth factor (VEGF) pathway induce the accumulation of monocytes and neutrophils. Shortly after, it was obvious that this buildup of non-classical monocytes was responsible for the development of an immunosuppressive tumor microenvironment in colorectal cancer.
The team identified the signaling pathway by which VEGF blockade induces expression of a molecule termed CX3CL1 on tumor cells, attracting non-classical monocytes that carry the matching receptor. Consequently, those cells attract neutrophils with another molecule termed CXCL5; and both immune cells express factors that inhibit the proliferation of T cells, reducing the overall immune response to the tumor. Biopsy samples taken from human patients before and after anti-angiogenic therapy were examined. The team demonstrated that expression of these chemokines increased in response to anti-VEGF treatment.
To develop a potential gene therapy approach, the team collaborated with researchers from Massachusetts Institute of Technology (MA, USA). By utilizing nanoparticle-delivered RNA interference against the interaction between CX3CL1 and its receptor, the team significantly reduced the infiltration of non-classical monocytes into treated tumors and increased the beneficial effects of anti-VEGF therapy in a mouse model.
“Targeting resistance mechanisms can improve the efficacy of anti-angiogenic therapy drugs and help fulfill their promise against cancer,” concluded Fukumura. “Our study’s unveiling of a novel resistance mechanism to anti-VEGF therapy and the molecular mechanism underlying that resistance offers a basis for the development of novel and efficient immunotherapeutic strategies to treat solid tumors.”