A new dawn in the late stage of alveolar echinococcosis “parasite cancer”

Abstract

Recently, it is found that there is high concentration of potassium in tumor interstitial fluid, which causes “T cell exhaustion” and even autophagy of lymphocytes in tumors. The immune mechanism of the late stage of alveolar echinococcosis (AE) is similar to that of tumor immunity. We speculate that the growth and development of the worm body, the necrosis of the worm body and the release of high concentrations of potassium after hepatocyte necrosis in the pathological process of AE may cause “T cell exhaustion” in AE patients. If this assumption can be confirmed experimentally, T cell adoptive transfer around the AE infiltration zone will be utilized to assist the treatment of AE patients with complex conditions.

Introduction

Alveolar echinococcosis (AE) is also known as the “parasite cancer” because its growth pattern is similar to that of malignant tumors. It is a zoonosis caused by the infection of Echinococcus multilocularis. In the world, 91% of the cases occur in the Qinghai-Tibet Plateau of China [1]. As one of the most lethal chronic parasites in the world, AE excision rates are 20–50% in the European cohort [2] and more than 90% of patients die in 10–15 years without treatment [3]. In addition, E. multilocularis is also the smallest parasite in tapeworms, which has high variability, and, can live in both anaerobic and aerobic environments [3]. Its larvae can parasitize rodents and humans. E. multilocularis is only found in the northern hemisphere [3] and is also likely to undergo subtle changes in the arctic due to climate change [4]. Currently, echinococcosis is listed by WHO as a zoonosis neglected by humans [2], [3].

Immune response of AE

A case of AE with HIV was reported in Beijing in 2017 [5]. The AE latency of this patient was 1.5 years, much shorter than that of other AE patients (10 years) [6]. Adrien et al collected 50 AE cases with immunosuppression associated conditions (including HIV) from 1982 to 2012 at the French AE Registry and found that patients with immunosuppression were at increased risk for progression of AE [7]. Some experts believe that the immune response of AE is divided into three stages. The early stage is the period in which both Th1 and Th2 participate. A dominant Th2/Treg profile, including regulatory cytokines, is found at the chronic middle stage. The late stage is the T-cell exhaustion period. Numerous animal experiments have shown that AE lesion grows faster in the middle and late stages [8], [9]. Zhang et al. hypothesized that the phenomenon commonly called ‘T cell exhaustion’ could play a role in the middle and late stages of AE [10]. The T-cell exhaustion period is also noted in tumor immunity [11]. However, the underlying mechanisms are unclear.

T cells and potassium

Changes in potential on the cell membrane enable the cells to perform normal physiological activities. Maybe the tumor cells have normal physiological activities at first, but when the tumor tissue grows to a certain extent, the rules are not so obvious. Surprisingly, this happens to be an important mechanism for tumor immunity. However, the mechanism underlying “T cell exhaustion” in tumor lesions is unclear. The results of Suman et al. showed that there were many ischemic and necrotic tumor cells in the tumor microenvironment, which released the potassium-rich cell fluid after rupture [12]. When T cells phagocytose or destroy tumor cells, they must first contact with the interstitial fluid, which has high concentrations of potassium. These T cells will undergo metabolic changes due to changes in the potential on cell membrane. The metabolic changes is including the reduction of the nucleo-cytosolic AcCoA. And the AcCoA leads to epigenetic changes, resulting in functional heat limitation and even autophagy. However, some of the surviving Tumor-infiltrating lymphocytes (TILs) retain the dryness of T cells, and they have a strong anti-tumor ability after adoptive transfer in non-high potassium environments [13], [14]. And, they can significantly reduce the size of large metastatic foci (in mice) [12]. Suman et al. have confirmed that both CD8⁺ T cells and CD4⁺ T cells have such effects [12].

Potassium in AE lesions

As early as 1923, Gordon et al. had demonstrated that through Macallum's technique, the cystic walls (including the cystic walls of mother, daughter and granddaughter cysts) of cystic echinococcosis (CE) and protoscolex contained high concentrations of potassium [15]. In 2013, Li et al. found that the K⁺ concentration was 216.76 ± 2.85 mg/L in CE cystic liquid by atomic emission spectrometry, slightly higher than that in plasma [16]. Gordon et al. speculated that the slightly high concentration of potassium in CE was caused by the secretion of potassium from the wall of CE cyst [15]. AE lesions will have more cyst cavitys than CE, if both of them have the same volume. In terms of the number of AE cysts, the wall area of AE cysts is obviously much larger than that of CE. Thus, the potassium concentration in AE lesions is higher than that of CE, and since AE growth is invasive and may cause tissue necrosis, the potassium concentration in AE “infiltration zone” would be closer to that in tumor microenvironment. We will use tissue centrifugation method (a way for tumor interstitial fluid isolation) [17] to isolate AE lesion interstitial fluid. And then measure the concentration of AE lesion potassium by the inductively coupled plasma atomic emission spectrometer (ICP-AES).

https://doi.org/10.1016/j.mehy.2020.109735

High potassium levels silence T cells in tumors

Many tumors contain lurking immune cells, including T cells that are equipped to attack the cancerous tissue. But the chemistry inside the tumor silences these T cells, allowing the cancer to persist and grow.

A team of scientists report that high levels of potassium ions are part of the tumor chemistry that blocks T cell activity. The researchers found that engineering T cells to adjust to these high potassium concentrations improved the cells’ ability to attack tumors in mice (Nature 2016, DOI: 10.1038/nature19364).

These findings add to a growing list of mechanisms that cancers use to evade recognition by the immune system. For example, tumors hijack native signaling molecules called immune checkpoints to inhibit the activation of T cells. In the past several years, the U.S. Food & Drug Administration has approved therapies that block these checkpoint molecules.

Nicholas P. Restifo and colleagues at the National Cancer Institute have been studying how basic aspects of cell function, such as metabolism, affect immune cell function. They decided to study potassium ion levels in the fluid inside tumors based on insights from cancer surgeons. “When you operate on a tumor and take it out and cut through it, it can have liquefied necrotic areas within the tumor,” Restifo says. So the researchers wondered what the impact of these inner dying cells had on the tumor environment.

One of Restifo’s postdocs, Robert Eil, currently at Oregon Health & Sciences University, hypothesized that these dying cells were spilling potassium ions into tumors. That’s because all cells, including cancerous ones, maintain a concentration gradient across their membranes, with low concentrations of potassium ions outside and high concentrations inside. “They’re bags of potassium,” Restifo says.

When the researchers analyzed the fluid inside mouse and human tumors, they found that potassium ion levels were elevated relative to those outside the tumors. In cell culture studies, T cells bathed in such high potassium concentrations mounted smaller responses to antigens than did cells exposed to average potassium levels.

Typically, when T cells encounter their target antigen, they release cytokines to signal other immune cells to attack. Through a series of experiments, the scientists found that the high extracellular potassium ion concentrations cause intracellular levels of the ion to increase, which in turn disrupts the signaling pathway necessary to trigger a normal cytokine response.

The researchers determined that T cells could still respond to antigens in high potassium solutions if the cells got some help with exporting some of their intracellular potassium. The scientists accomplished this by engineering the cells to express large numbers of a protein channel that allows potassium ions to flow out of the cell. Mice injected with such engineered T cells were better at attacking the tumors and survived longer than mice receiving nonengineered cells.

“[The] findings have potentially paved the way for therapies that enhance the ability of our immune systems to combat cancers,” write K. George Chandy of Nanyang Technological University and Raymond S. Norton of Monash University in a perspective that accompanies the paper in Nature.

Chandy and Norton wonder if molecules that enhance the activity of protein channels similar to the one in this study could help restore T cell function deep inside tumors.

Eil thinks the findings could enhance therapies in which a patient’s own immune cells are reprogrammed to target tumor cells. Such therapies are already in clinical trials. Engineering the reprogrammed cells to better respond to high potassium levels, Eil says, could increase their efficacy.

https://cen.acs.org/articles/94/i37/High-potassium-levels-silence-T.html

Echinococcosis is a parasitic disease of tapeworms of the Echinococcus type. The two main types of the disease are cystic echinococcosis and alveolar echinococcosis. The most common form of treatment is open surgical removal of the cysts combined with chemotherapy using albendazole or mebendazole before and after surgery.

Albendazole and mebendazole are the only anthelmintics effective against cystic echinococcosis. Albendazole is the drug of choice against this disease because its degree of systemic absorption and penetration into hydatid cysts is superior to that of mebendazole.

The effect of albendazole on potassium channels is unknown, however it appears that albendazole may increase plasma potassium levels.

Effects of ivermectin and albendazole on some liver and kidney function indices in rats

Evaluation of repeated administration of ivermectin and albendazole separately and in combination on some hepatic and renal function indices were examined in albino rats (Rattus novergicus). The experimental animals were randomly divided into four groups: those administered distilled water (control), those administered 0.4 mg/kg (or 0.06 mg/kg in human) body weight of ivermectin (Iver), those administered 15 mg/kg (or 2.43 mg/kg in human) body weight of albendazole (Alb) and those administered the two drugs concurrently (Iver+Alb). The animals were administered, the drugs daily for fifteen days after which venous blood, liver and kidney were collected. The separate administration of ivermectin and albendazole significantly elevated the concentrations of serum potassium and bicarbonate ions. Also, their co-administration caused a significant elevation of serum phosphate ion concentration. Administration of ivermectin and/or albendazole led to significant increase in serum urea, creatinine, glucose and cholesterol concentrations while albumin was significantly reduced. Generally, activities of ALP, ACP, LDH, AST, ALT, Na+ -K + ATPase and Ca2+ -Mg2+ ATPase of liver and kidney were significantly altered. These observations may be suggestive of deranged membrane structures and functions. Thus the combined administration of the two drugs may be exerting more deleterious effects on both renal and hepatic functions than when administered individually.

https://internationalscholarsjournals.com/abstract/effects-of-ivermectin-and-albendazole-on-some-liver-and-kidney-function-indices-in-rats-55202.html

Perhaps other echinococcosis treatment options for cancer can also be used. Fluralaner, a potent chloride channel blocker and an insecticide and acaricide with antiparasitic activity against cat and dog fleas and ticks, may be one such option!

https://link.springer.com/article/10.1007/s12639-020-01224-6