The Relationship Between The Endocannabinoid System, Phytocannabinoids, The Immune System, and Cancer
The immune system is tremendously complex, and its key components include numerous types of white blood cells, called leukocytes, that specialize in different aspects of defense. There are specialized leukocytes for killing bacteria, releasing antibodies, and destroying cells infected with viruses, although most leukocytes have overlapping functions. Certain types are also programmed to eliminate cancer cells by recognizing changes in molecules on their cell membranes. However, cancer cells are clearly able to bypass immune defenses in any case where cancer grows to a diagnosable level.
Immunotherapy is a growing field of oncology that uses drugs to restore or boost the ability of the immune system to fight cancer. These therapies hold promise for treating cancers that are resistant to chemotherapy and radiation. Some evidence suggests that natural compounds like phytocannabinoids derived from cannabis may stimulate anticancer functions of the immune system, in addition to their more well-defined actions of directly killing cancer cells and inhibiting proliferation.
The Immune System and Cancer
Cells of the immune system can be broken down into those of myeloid lineage and lymphoid lineage. Myeloid lineage immune cells include neutrophils, the most numerous type of immune cell in the body, which seek out and destroy microorganisms. Other myeloid cells include macrophages, which are longer-lived than neutrophils and clear away many kinds of cellular debris in addition to ingesting and killing microorganisms. Lymphoid cells (lymphocytes) include natural killer (NK) cells, B cells, and T cells. B cells are distinct for their ability to produce antibodies, which help other leukocytes and immune system components kill invading cells; they are activated specifically by helper T cells.
Another type of T cell, the cytotoxic T cell, shares the ability of NK cells to kill virus-infected cells or cancer cells, although T cells require activation by other cells whereas NK cells do not. However, many cancer cells are resistant to regular NK cells or cytotoxic T-cells, but a special type of lymphocyte known as a lymphokine-activated killer cell (LAK cell) can destroy some resistant cancer cells. LAK cells appear to derive from either NK cells or a subtype of T-cells, and can share some features with either type of precursor cell. The most important feature of LAK cells is their greater ability to kill tumor cells. Thus, they are a major focus of potential immunotherapy approaches.
How CBD and THC Interact with the Immune System and Cancer
Research suggests that phytocannabinoids may improve the efficiency of LAK-mediated cancer cell destruction. A 2014 study published in Biochemical Pharmacology applied cannabidiol (CBD) to lung cancer cells and found that it caused the increase of intercellular adhesion molecule-1 (ICAM-1) on the surface of the cancer cells. ICAM-1, as the name implies, can help cells adhere to each other, and is involved in many biological processes. The increase in ICAM-1 caused cancer cells to become more susceptible to lysis (cell breakdown and destruction) by LAK cells, as there were essentially more targets for the LAK cells to bind to. Specifically, the LAK cells appeared to bind to ICAM-1 through lymphocyte function-associated antigen 1 (LFA-1), a protein on leukocytes that facilitates their adhesion to other cells. Tetrahydrocannabinol (THC) and an analog of the endocannabinoid anandamide also increased ICAM-1 levels and led to increased killing of cancer cells by LAK cells, although the level of ICAM-1 increase was less than that induced by CBD. Importantly, all three cannabinoids had very little to no effect on ICAM-1 levels in healthy lung cells and did not lead to increases in LAK-mediated lysis of those cells. Both cannabinoid receptors, CB1 and CB2, were integral to the increased ICAM-1.
A 2019 study by researchers from the United States and Japan examined how CBD interacted with immunotherapy treatment for Burkitt lymphoma (BL). BL cell lines were altered to express higher levels of a protein called AF1q, which drives cancer growth and confers resistance against immunotherapeutic drugs. The mechanism of resistance was posited to be reduction of ICAM-1 expression, and apparently by increasing ICAM-1, CBD reversed drug resistance. The authors concluded, “CBD holds potential to enhance the efficacy of immunotherapy for BL.”
THC possesses well-demonstrated anti-inflammatory properties, which appear to exert some inhibitory effects against skin cancer. A 2015 study by researchers with the University of Bonn in Germany applied THC to two mouse melanoma cell lines, finding that THC had no effect on cell proliferation. However, when the cells were injected into mice and tumors developed, THC-treated mice had 50% smaller tumor volumes. The shrinkage was due to reduced infiltration of macrophages and neutrophils. Therefore, the anticancer effects in this case seemed to be largely driven by effects on the immune system.
CBD has also been shown to reduce breast tumor growth and metastasis at least partially through anti-inflammatory effects. A 2015 study conducted at Ohio State University determined that CBD impaired the recruitment of tumor-associated macrophages in primary tumors and lung metastases in mice through reduced production of pro-inflammatory cytokines. Tumor-associated macrophages are involved in pro-tumor effects like generation of blood vessels to tumors, enhanced tumor cell invasion, and suppression of anticancer functions of NK cells and T-cells.
Another benefit was revealed in a 2020 study published in the International Journal of Molecular Sciences, which examined the effects of THC and CBD on pancreatic cancer cell growth. Both phytocannabinoids were effective at inhibiting proliferation of the isolated cancer cells as well as suppressing tumor growth in mice. The anticancer effect was apparently at least partially through reduction of an immune checkpoint pathway. Such pathways help regulate the immune system and prevent excessive activation. The checkpoint affected was the PD-1/PD-L1 pathway, which involves the binding of a molecule called programmed death-ligand 1 (PD-L1) to programmed cell death protein-1 (PD-1) on T-cells to cause inactivation and death. This is normally a healthy process, but when cancer cells overexpress PD-L1, they stop T-cells before they can carry out their anticancer functions. In fact, blocking PD-1 on T-cells is a key target of immunotherapy drugs, including nivolumab which is further discussed below. Therefore, the demonstrated ability of both THC and CBD to reduce expression of PD-L1 on pancreatic cancer cells may help T-cells destroy them. The researchers stated, “The inhibition of PD-L1 expression by CBD and THC will enhance the anti-tumour immune response induced by immune checkpoint blockade in pancreatic cancer.”
The effects of phytocannabinoids on the PD-L1/PD-1 pathway may extend to other cancers, as CBD has also been shown to reduce PD-L1 on the surface of glioblastoma cells, which was reportedly associated with increased cell death of the cancer cells.
THC’s anti-inflammatory and immunosuppressive effects are not always linked to good outcomes. In 2000, researchers from the University of California, Los Angeles, School of Medicine administered THC to mice with lung cancer and found that it accelerated tumor growth. This effect was linked to THC-induced increase of anti-inflammatory cytokines (IL-10 and TGF-beta) and a decrease in interferon-gamma, an immune system protein involved in antitumor effects. The activation of CB2 receptors by THC was the apparent cause of modulated cytokine expression.
Similar results were reported in a 2005 study, where THC enhanced tumor growth in a mouse model of breast cancer by suppression of the antitumor immune response via CB2 activation and enhancement of the anti-inflammatory cytokines IL-4 and IL-10.
The immunosuppressive effects of THC may be relevant in regards to interfering with immunotherapy. A 2019 study conducted in Israel examined patients with melanoma, non-small cell lung cancer, and renal clear cell cancer who used the immunotherapy drug nivolumab with or without predominantly THC-rich cannabis. Cannabis use was associated with a reduced response rate to the immunotherapy drug, although it did not affect the key outcomes of progression-free survival or overall survival. Quite interestingly, the authors noted a “possible paradoxical interaction related to THC level, as patients who had high‐THC‐percentage products had a better [response rate] to immunotherapy compared with those with low‐THC‐percentage products.”
It is also somewhat paradoxical that THC shows interference with nivolumab, as this immunotherapy drug works by blocking PD-1, the target of PD-L1, the latter of which is shown to be inhibited by THC in pancreatic cancer cells. Also, despite THC’s interference with response to the drug, no impact on patient survival was seen, potentially indicating THC was working against the cancer in other ways. In addition, since this study did not include pancreatic cancer patients, it may be that THC would show better results in that cancer type, so more research is critical to ascertain if synergy may be observed in that or other cancers. In any case, special care must be taken when using any phytocannabinoids alongside immunotherapy drugs due to the real potential for negative interactions.
Overall, the ability of phytocannabinoids to reduce inflammation may help prevent the development of some cancers. However, evidence also shows that phytocannabinoids, especially THC, may facilitate cancer development through immune system suppression, so more research is needed to clarify when the effects are beneficial or detrimental.
How 2-AG Interacts with the Immune System and Cancer
The previously mentioned study of CBD and THC upregulating ICAM-1 pointed to the potential of anandamide to work with the immune system to improve clearance of cancer cells. The other primary endocannabinoid, 2-arachidonoyl glycerol (2-AG), may also help the immune system fight cancer, although the effects are less clear. A study published in 2019 found that 2-AG substantially reduced pancreatic tumor growth in mice via activation of CB1 receptors. 2-AG also promoted the maturation of dendritic cells (DCs) via CB1 receptor activation. DCs help activate T-cells and trigger antitumor activity, and are a growing target of immunotherapy. However, the DC maturation was only observed in isolated DCs and in vivo mouse spleen DCs, not tumor tissue. Other immune cells called myeloid-derived suppressor cells (MDSCs) which suppress T-cells and are linked to tumor progression were increased in tumor tissues after 2-AG administration.
Although the immune effects of 2-AG are inconsistent, the fact that 2-AG effectively suppressed growth of pancreatic tumors in mice suggests that its anticancer effect is greater than any potential procancer effect. It seems that the positive impact of 2-AG on DC maturation outside the tumor, or the direct antiproliferative effects on pancreatic cancer cells themselves, outweighs the negative impact of increasing MDSCs. The researchers noted that gemcitabine, a chemotherapy drug used for pancreatic cancer that reduces MDSCs, may be effectively combined with 2-AG for synergy. Despite the disparate impacts on immune function, it was still suggested that 2-AG “may be a promising new drug for cancer immunotherapy.”
An earlier study in 2015 in the journal Life Sciences also demonstrated conflicting effects of 2-AG on the immune microenvironment surrounding tumors. In bladder cancer cells, the activation of CB1 and CB2 receptors by 2-AG resulted in several immunological effects. Secretion of tumor necrosis factor-alpha (TNF-α), a small signaling protein (cytokine) involved in inflammation, was increased, as was the expression of selectins on the surface of the cancer cells, which are involved in adhesion. The selectin increase may have explained the third observation; the adherence of T-cells to cancer cells. However, selectins are largely associated with metastasis, whereas TNF-α is linked with both pro- and anti-tumoral effects. While the role of 2-AG in bladder cancer progression is especially unclear, more research is needed with animals, as the function of cannabinoids in living organisms can often be quite different than observed in cells. For example, although 2-AG was associated with the theoretically negative effect of increasing MDSCs in pancreatic cancer tumors in a previously mentioned study, administration of the endocannabinoid in mice shrunk the tumors, indicating a net anticancer effect.
The Role of Cannabinoid Receptors in the Immune System and Cancer
The development of blood vessels to tumors, known as angiogenesis, is integral to the continued growth of solid cancers past a certain point. Macrophages contribute to angiogenesis by releasing compounds that drive the growth of new blood vessels to tumors. A 2016 study determined that activation of CB1 and CB2 receptors on human lung macrophages with synthetic cannabinoids reduced the release of numerous growth factors like vascular endothelial growth factor-A, vascular endothelial growth factor-C, and angiopoietins (Ang1 and Ang2). However, activation of receptors by 2-AG was not effective in decreasing these compounds, although the researchers stated that 2-AG might affect other aspects of macrophage function not tested in this study. In any case, the inhibition of vascular remodeling induced by macrophages may be another mechanism by which cannabinoid receptors interfere with tumor growth.
Further evidence for the function of cannabinoid receptors in facilitating anticancer functions of the immune system was revealed in a 2016 study by researchers from the United States, Germany, and South Korea. It examined the disparate impact of CB1 and CB2 receptors on the development of hepatocellular carcinoma (HCC), a form of liver cancer. The CB1 receptor was associated with cancer development while the CB2 receptor was associated with blocking cancer development, as indicated by experiments where CB1 or CB2 receptors were inactivated in mice. Specifically, CB2 receptor inactivation decreased recruitment of hepatic T-cells with known antitumor effects by reducing expression of cytokines. Therefore, it appears that the CB2 receptor is involved with helping recruit T-cells to liver tumors to fight them.
Phytocannabinoids and Cancers of the Immune System
Leukemias and lymphomas are cancers of the immune system which involve various immune cells that begin replicating in an uncontrolled manner and fail to develop into healthy, functional cells. In 2005, researchers in London demonstrated that THC induced apoptosis (programmed cell death) in three leukemia cell lines. The next year, a study showed CBD induced apoptosis in both leukemia and lymphoma cells. Importantly, CBD reduced the size of lymphoma tumors in mice, indicating that even in the context of the living tumor microenvironment it was still effective.
Yet further, the phytocannabinoids CBD, cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigevarin (CBGV), and cannabigevaric acid (CBGVA) were shown in a 2013 study published in Anticancer Research to stop the proliferation of leukemia cells, although CBD and CBG were the most potent among those compounds.
Summary
There is clearly a quite complex relationship between endocannabinoids, phytocannabinoids, the immune system, and cancer, as evidenced especially by the ability of THC to either promote or inhibit cancer growth through immune system interactions. Despite the negative observed effects of THC, most studies indicate anticancer effects of THC in both cell and animal studies, not to mention human cases. Furthermore, the latest meta-analysis of cannabis use and cancer risk, published in August 2020, found that cannabis use was associated with a slightly reduced risk of most cancers, except for testicular cancer. The most reasonable explanation is that the anticancer functions of THC, other phytocannabinoids, and terpenes overwhelm immunosuppressive effects of THC and the carcinogenic properties of compounds in cannabis smoke.
