Hepatic stellate cells suppress natural killer cells allowing cancers cells to ‘wake up’
Natural killer (NK) cells are specialized white blood cells crucial for fighting cancer and a first line of defense against infection. Robust activity of NK cells is necessary to keep cancer cells dormant and oppose metastasis. New evidence has emerged showing how metabolic factors that promote liver fibrosis result in the suppression of healthy NK cell activity.
Natural killer cells keep cancer cells dormant
A study recently published in the journal Nature reveals how the increase in NK cell activity that keeps cancer cells dormant is opposed by hepatic (liver) stellate cells. The authors state:
“The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment1,2,3. These enduring dormant DTCs are seeds of future metastases, and the mechanisms that switch them from dormancy to outgrowth require definition. Because cancer dormancy provides a unique therapeutic window for preventing metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of reservoirs of dormant DTCs is imperative.”
They demonstrate that interferon-γ signaling by NK cells sustains the dormancy of breast cancer cells thus preventing metastases, but when the NK cells population contracts the cancer cells are permitted to ‘wake up’ from their dormant state.
A review of the study published by the University of Basel where the work was performed quotes Professor Mohamed Bentires-Alj, group leader at the Department of Biomedicine at the University of Basel and University Hospital Basel:
“This dormancy period offers an important therapeutic window in which the number of cancer cells and their heterogeneity are still manageable…Understanding the cellular and molecular mechanisms underlying tumor dormancy is therefore crucial to preventing the recurrence of cancer.”
Additional comments published by reviewers in Nature under ‘Natural killer cells lull tumours into dormancy’ elaborate on the significance of these findings.
“Several studies have suggested that NK cells specialize in eliminating metastases rather than targeting tumour cells at their primary site of growth6. For some cancers, people who have more tumour-infiltrating NK cells seem to have fewer metastases, as seen in those with cancers such as gastrointestinal sarcoma, and gastric, colorectal, renal or prostate carcinoma3,6. The depletion or dysfunction of NK cells in mice also results in an increase in metastases3…and found that NK cells were the only type of immune cell to increase in number during dormancy. This suggests that NK cells have a crucial role in events that block the reawakening of dormant tumour cells (Fig. 1).”
“…depleting NK cells…led to higher levels of metastases in the liver. However, if NK cells were boosted using the cytokine IL-15, this prevented the formation of liver metastases and tumour cells remained dormant…the size of the pool of NK cells in the liver environment determines whether dormancy occurs or metastases form.”
Quoted by the University of Basel, lead author Dr. Anna Correia states:
“These cells are a natural barrier against metastasis in the liver. If they could be used to prevent the development of metastases in other parts of the body, too, it might be possible to permanently prevent the recurrence of cancer.”
Hepatic stellate cells suppress natural killer cells
Hepatic stellate cells (aHSCs) reside in the liver between liver cells and the small blood vessels servicing them. They are activated by liver damage to secrete the collagen that forms the scar tissue of chronic fibrosis (cirrhosis). A salient discovery of these researchers is that activation of hepatic stellate cells results in the suppression of natural killer cell activity.
“Exit from dormancy [of cancer cells] follows a marked contraction of the NK cell compartment and the concurrent accumulation of activated hepatic stellate cells (aHSCs)…Our data identify the interplay between NK cells and aHSCs as a master switch of cancer dormancy, and suggest that therapies aimed at normalizing the NK cell pool might succeed in preventing metastatic outgrowth.”
Dr. Correia is further quoted by the University of Basel:
“There can be various reasons why hepatic stellate cells are activated; for example, chronic inflammation in the body or persistent infection.”
This draws our attention to what is the most common consequence of hepatic stellate cell inducement—metabolic liver fibrosis. In a study published in Scientific Reports, the authors state:
“Hepatic fibrosis is a major consequence of chronic liver disease such as non-alcoholic steatohepatitis which is undergoing a dramatic evolution given the obesity progression worldwide, and has no treatment to date. Hepatic stellate cells (HSCs) play a key role in the fibrosis process, because in chronic liver damage, they transdifferentiate from a “quiescent” to an “activated” phenotype responsible for most the collagen deposition in liver tissue.”
Importantly…
“Moreover, we have also shown its relevance in human liver fibrosis associated with different etiologies (obesity, non-alcoholic steatohepatitis, viral hepatitis C and alcoholism). In particular, we have demonstrated a significant positive correlation between the stage of liver fibrosis and HSC hypertrophy in a cohort of obese patients with hepatic fibrosis. These results lead us to conclude that hypertrophied HSCs are closely associated with hepatic fibrosis in a metabolic disease context and may represent a new marker of metabolic liver disease progression…Frequency of HSC hypertrophy is related to the degree of fibrosis.”
This is the salient connection: Metabolic stress and/or inflammation in the liver drive hepatic stellate cell hypertrophy that suppresses natural killer cells, permitting cancer cells to ‘wake up’ from dormancy.
Interestingly, suppression of NK cell activity by activated hepatic stellate cells was documented in a paper published earlier in Scientific Reports. These authors highlighted the role of the cytokine TGF-β (transforming growth factor beta) in driving the associated fibrosis.
“These data suggested that fully activated α-SMA+ HSCs produce a large amount of TGF-β that subsequently deactivates NK cells and inhibits their anti-fibrotic effect, particularly in advanced LC patients…Taken together, these findings suggested that HSCs have a great impact on hepatic NK cell anti-fibrotic functions via TGF-β, which suppresses NK cells’ killing capacity and IFN-γ production, and induces NK apoptosis…”
“…the increased TGF-β levels in the livers of LC patients might inhibit NK cell cytolytic activity and IFN-γ production, since blockade of TGF-β significantly enhanced NK functions in vitro. Indeed, in a mouse model, intermediately activated HSCs could produce more TGF-β and inhibit IFN-γ production of NK cells compared with early-activated HSCs, and blocking TGF-β also restored NK cell killing and IFN-γ production23.”
Opposing hepatic stellate cell expansion and liver fibrosis
In a paper published in the World Journal of Gastroenterology, after reviewing the pathological hallmarks of liver fibrosis and hepatic stellate cell pathology including the role of TGF-β, the authors discuss therapeutic targets to suppress HSC activity. These include ursolic acid, 24-nor-ursodeoxycholic acid, and resveratrol. Regarding the latter, which has additional virtues that including promoting SIRT2 and opposing NFkB to block inflammasome activity, and induction of malignant cell apoptosis, they state:
“…the natural polyphenol flavonoid resveratrol has a broad range of beneficial biological functions…”
“…including anti-inflammatory[97] and antioxidant[98] properties[99]. In addition, resveratrol is believed to ameliorate obesity-related complications by mimicking caloric restriction[100] through activation of key metabolic regulators, including NAD+-dependent deacetylase (SIRT1)[101], AMP-activated protein kinase[102], and nuclear factor erythroid-2 related factor 2[103]. Furthermore, oxidative damage and inflammation are closely related to the HSC activation process…Moreover, studies have demonstrated the beneficial effects of resveratrol in different models of liver steatosis[105-108]. Superoxide dismutase activity is necessary for the reduction of oxygen free radicals and protects against lipid peroxidation, thereby inhibiting HSC activation and limiting the progression of liver fibrosis[109].”
Fueling natural killer cells is impaired by metabolic syndrome
NK cells need fuel to engage in the work of making cancer cells dormant. How they are fueled is described a study conducted at Memorial Sloan Kettering recently published in Cell Reports that reveals the central role of glycolysis in NK metabolism.
This is relevant to the connection between liver fibrosis and NK cell suppression because insulin resistance that drives fatty liver disease also impairs delivery of glucose to NK cells. The authors state how they revealed the manner in which the metabolic demands of NK cells are met by observing the function of the enzyme lactate dehydrogenase A (LDHA). The same processes that damage the metabolic fitness of NK cells also drive the expansion of hepatic stellate cells.
“Natural killer (NK) cells are…capable of rapid cytotoxicity, cytokine secretion, and clonal expansion. To sustain such energetically demanding processes, NK cells must increase their metabolic capacity upon activation. …we investigated the role of aerobic glycolysis in NK cell function and demonstrate that their glycolytic rate increases rapidly following viral infection and inflammation, prior to that of CD8+ T cells.”
LDHA-deficient NK cells are defective in their anti-viral and anti-tumor protection. These findings suggest that aerobic glycolysis is a hallmark of NK cell activation that is key to their function.
This corresponds to the fact that metabolic syndrome is a known significant risk factor for common cancers (e.g., liver, colorectal, breast, endometrium, pancreas)4,5.
As reported in Memorial Sloan Kettering Cancer Center website:
“When an NK cell becomes activated, they massively increase their glycolysis,” Dr. Sheppard says. “In the case of viral infection, this happens within just two days.”
Aerobic glycolysis is so important to the cells, in fact, that when the researchers genetically altered the mice to remove a key component of this pathway, called LDHA, the NK cells were useless.
“They can still develop normally and carry out most of their day-to-day functions,” Dr. Sun says. “But their ability to fight infections and cancer is crippled.”
They found that NK cells ramp up aerobic glycolysis about five days prior to when T cells respond with their own glycolytic surge.
The findings are relevant to ongoing efforts to use NK cells as immunotherapy in people with cancer and other conditions.
Clinical Summary
NK (natural killer) cells act to prevent metastases by keeping cancer cells in a state of dormancy. Expansion of hepatic stellate cells suppresses NK cell activity as the HSCs engage in the process of fibrosis. Insulin resistance promotes fatty liver disease and drives fibrosis while impairing the metabolic fitness of NK cells by impairing access to the glucose they need for glycolysis. Glutathione offers cellular protection while opposing TGF-β; resveratrol acts dampens TGF-β, the NFkB inflammasome, acts against cancer stem cells and promotes apoptosis, and enhances the response to insulin making glucose available to NK cells for glycolysis.
