Immune-endocannabinoid system and tumor microenvironment

Cannabis has been used for the treatment of a variety of diseases in traditional medicine. Not long ago, researchers discovered that our own body produces substances that affect our health the same way as Cannabis does. These substances were called endocannabinoids, and together with all molecules of our organism that respond to and produce endocannabinoids, they were merged into a new physiological entity, the so-called endocannabinoid system. Cells of our immune system are integral part of tumors and major determinants of tumor growth. Since the endocannabinoid system is present in many immune cells, we investigate in our project whether this immune-endocannabinoid system has an impact on tumor growth. Our hypothesis is that the components of this system are involved in the functional regulation and behavior of immune cells within the tumor which ultimately affects tumor growth. We will use mice that are deficient of certain components of the endocannabinoid system and study tumor growth in established preclinical cancer models. We will use different tumor cells lines and investigate in cell culture experiments whether components of the endocannabinoid system affect proliferation and differentiation of immune cells. By use of a specific detection system we will localize these components in the tumor in histologic sections and determine the cells in which they are expressed. The expression of the endocannabinoid system and its presence in immune cells will be also investigated in human samples of lung and colon cancer. We will finally test whether (endo) cannabinoids are helpful for antitumor therapy with checkpoint inhibitors and chemotherapeutics. Although it is known from earlier studies that cannabinoids, such as tetrahydrocannabinol (THC) which is the psychoactive ingredient of Cannabis, can influence the behavior of immune cells, it is still elusive how the endocannabinoid system affects tumor growth. From these new data we expect to create a basis for using (endo)cannabinoids as antitumor agents and components of the endocannabinoid system as therapeutic targets and whether endocannabinoids assist or hamper an immune- or chemotherapy.

The endocannabinoid system of the tumor microenvironment controls tumor growth Cannabis has been used as a traditional remedy for thousands of years. The mechanisms behind its effects have been only recently investigated and led to the description of the so-called "endocannabinoid system" (ECS) which includes cannabinoid receptors, their activating molecules (so-called "endocannabinoids"), and the endocannabinoids' producing and degrading enzymes. It came to a surprise that humans and animals produce endocannabinoids that are able to activate cannabinoid receptors much like ingredients of the Cannabis plant do. The ECS controls many aspects of our body functions, such as mood, appetite and metabolism. It also protects us from inflammation, and additionally plays a role in tumor growth. However, it is still unclear how. Solid tumors not only consist of tumor cells, but also immune cells that infiltrate the tumor during its growth, and make up most of the tumor microenvironment. Like in inflammation, the immune cells' purpose is to fight off tumor growth. Most of these immune cells express cannabinoid receptors, and they have enzymatic machinery to produce and degrade endocannabinoids which control many functions of these immune cells. Our project intended to unravel the role of the ECS in the tumor microenvironment. Knowledge of its influence on tumor growth may be of importance for improving immunotherapy with antibodies. Several tumor models were used to investigate the role of ECS components on tumor growth. In a lung cancer model, we could show that the deficiency of a cannabinoid receptor, or an endocannabinoid-degrading enzyme in cells of the tumor microenvironment, slowed tumor growth. At the same time, we noticed that more cancer cell-killing immune cells populated the tumor, and that the susceptibility to antibody-based immunotherapy was enhanced. This suggested that the components of the ECS in the tumor microenvironment suppress immune cell activity during tumor growth. Similarly, in a model of pancreatic cancer, we observed that deficiency of a cannabinoid-related receptor in cells of the tumor microenvironment led to smaller tumors. By analyzing the tumor tissue, we could reveal that, like in the lung cancer model, more tumor cell-killing immune cells were present in the tumors, and that molecules relevant for an intact immune response were much more frequently expressed. This suggested that certain components of the ECS may suppress activity of the immune system during tumor growth also in a pancreatic cancer model. In conclusion, blockade of certain cannabinoid receptors could be of advantage for releasing suppression on the immune system in the tumor microenvironment, which could be helpful during immunotherapy with antibodies.