טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentWyrobnik Iris
SubjectThe Effect of Cannabis on the Tumor Microenvironment
DepartmentDepartment of Biology
Supervisors Dr. David Meiri
Dr. Yishai Ofran
Full Thesis textFull thesis text - English Version


Abstract

The tumor microenvironment plays a critical role in the progression of the tumor. During cancer development, the cell composition and activity inside the microenvironment are constantly manipulated in the cancer's favor. The environment is changed in order to allow continuous growth and metastasis. One of the mechanisms to enable such changes is the recruitment and training of immunosuppressive cells, which decrease the functions of anti-cancer mechanisms of other effector immune cells. Because of the cancer's ability to do so, it is of great importance to not only develop anti-cancer drugs by targeting the cancer cells themselves, but also to achieve changes in the tumor microenvironment to weaken the tumor's ability to expand.

Cannabis is nowadays used for treating many different medical conditions, such as chronic pain, epilepsy, nausea and autoimmune disorders. In recent years, the anti-cancer effects of Cannabis are under strong examination, too. Phytocannabinoids have the ability to influence many different cell types, such as neurons and immune cells and therefore can also influence the tumor microenvironment. However, the effect of Cannabis on the tumor microenvironment immune cell composition and activity is poorly studied and still remains unclear. 

To investigate the effect of Cannabis extracts on the tumor microenvironment immune cell composition, we created a cancer model using WT C57BL/6 mice and transplanted the murine melanoma cell line B16-F10 subcutaneously. This model functions as an efficient tumor model to study the immune system inside the tumor microenvironment, since it causes a strong immune response and cell infiltrating cascade towards to the tumor.

Our work shows the decrease of tumor weight in-vivo in Cannabis treated mice; however, the high Δ9-THC strain reduces tumor size more effectively than the high CBD strain. Additionally, we identified changes in several myeloid populations in the tumor microenvironment in response to Cannabis treatment, while the lymphocyte percentage in spleen and tumor of the mice was not changed compared to the control. The high Δ9-THC extract increased the population size of the tissue-resident macrophages of the skin (dermal macrophages and Langerhans cells) compared to the high CBD extract and the control. Further, we identified the reduction of the monocytic MDSC subpopulation in the tumor microenvironment in response to Cannabis treatment compared to the control in-vivo. We also identified the specific reduction of M-CSF concentration in the intercellular solution of tumors from Cannabis treated mice.

These results suggest that the addition of Cannabis alters the myeloid cell composition in the tumor microenvironment. However, the high Δ9-THC and high CBD extracts have different effects on the myeloid cell composition. We conclude that with Cannabis treatment, the myeloid composition in the tumor microenvironment is changed to a less immunosuppressive milieu, which leads to reduced tumor size compared to the control group. Moreover, the differences in the myeloid composition between the high Δ9-THC and high CBD treatment might explain the differences in tumor size between the two treatments.