Parasites as potential targets for cancer immunotherapy

Abstract

Parasites and cancers have some common antigens. Much scientific evidence in the human population, animal models, and in vitro experiments exhibit that parasites have significant anti-cancer effects. The larval stage of the tapeworm Echinococcus granulosus, Toxoplasma gondii, Trypanosoma cruzy, Plasmodium’s, and Trichinella spiralis are among the parasites that have been subjects of anti-cancer research in the last decades. Anti-tumor effects of parasites may be due to the direct impact of the parasites per se or indirectly due to the immune response raised against common antigens between malignant cells and parasites. This manuscript reviews the anti-cancer effects of parasites and possible mechanisms of these effects. Options for using parasites or their antigens for cancer treatment in the future have been discussed.

Graphical abstract

Introduction

Approximately 18.1 million new cancer cases and 9.6 million cancer deaths worldwide were reported in 2018 (Bray et al. 2018). Conventional strategies for the treatment of cancers have not exhibited satisfying therapeutic outcomes. Also, these treatments cause a wide range of side effects, mainly due to killing normal cells and compromising the host’s immune system. Therefore, novel and more effective alternative therapeutic methods are urgently required. Parasites and cancers have some properties in common. For example, parasites and cancer cells use similar mechanisms for survival in their hosts. Indeed, when cancer cells lose their growth control, they may acquire parasitic features (Ashall 1986). On the other hand, some anti-cancer drugs have anti-parasitic effects and some anti-parasitic drugs have anti-cancer effects (Table 1). This mutual action of anti-parasites and anti-cancer for drugs might be related to some similar targets in parasites and cancer cells (Dorosti et al. 2014). Also, expression of common antigens such as N-acetylgalactosamine O-serine/threonine (Tn), sialyl-Tn, Thomsen Friedenreich (TF), and TK antigens have been reported in cancers and parasites by different studies (Darani and Yousefi 2012). Moreover, immunological cross-reaction between sera of cancer patients and parasites antigen has been reported (Daneshpour et al. 2016; Duan et al. 2013; Zenina et al. 2008; Ubillos et al. 2016).

Table 1.

Mutual action of anti-parasitic and anti-cancer drugs (Dorosti et al. 2014)

Drug	Main action	Mutual action
Depsipeptide	Anti-cancer	Anti-Leishmania
Imatinib	Anti-cancer	Anti-Echinococcus multilocularis cysts
Cisplatin	Anti-cancer	Anti-Leishmania, anti trypanosoma
Auranofin	Anti-cancer	Anti-Fasciola hepatica
Suramin	Anti-parasite	Activity against prostate cancer
Manzamine A	Anti-parasite	Activity against pancreatic cancer
Albendazole	Anti-parasite	Activity against different cancers

Although cancer cell-derived antigens are used for cancer immunotherapy, they are poorly immunogenic antigens (Bartnik et al. 2013). In contrast, antigens derived from microorganisms are usually very immunogenic. Therefore, using parasite-derived antigens with some degrees of homology with cancer antigens may compensate for the poor immunogenicity of cancer-derived antigens. So, these shared antigens with parasitic origin would be convenient candidates for cancer immunotherapy in future.

In many cancers, tolerogenic microenvironment presented by tumors inhibits effective anti-tumor immunity. Suppressive host immune cells such as Treg cells pose a significant challenge to cancer immunotherapy (Curiel 2007). It has been shown that immunization with certain parasites may overcome cancer immunosuppressive microenvironment. For example, plasmodium infection could inhibit the activation of Treg cells in the tumor microenvironment (Adah et al. 2019). So parasite antigens should overcome tolerance encountered with human-based cancer antigens (Noya et al. 2013) and may be able to change tumor immune suppressive microenvironment to the immune-supportive milieu (van den Boorn and Hartmann 2013).

Due to the typical characteristics of parasites and cancer and having common antigens, the more potent immunogenicity of the parasite, and the power of the parasite antigen in stimulating the immune system in cancer patients, parasites can be well-thought-out for cancer therapy in the future. So, in this paper anti-cancer effects of parasites have been reviewed.

Evidence about anti-cancer effects of parasites according to in vitro experiments

In vitro anti-cancer effects of the larval stage of Echinococcus granulosus (hydatid cyst), Trichinella spiralis, Toxoplasma gondii, Trypanosoma cruzi and Acanthamoeba castellani have been shown in various investigations. Different cancer cell lines were treated with protoscolices (Yousofi Darani et al. 2012), hydatid cyst fluid (Daneshpour et al. 2019), mucin-like peptides of Echinococcus granulosus (Noya et al. 2013) or sera of patients with hydatid cyst (Karadayi et al. 2013). All these treatments resulted in many cancer cells apoptosis induction and also cell death (Table 2). Regarding T. gondii, Choo et al. showed that Toxoplasma lysate antigen (TLA) inhibits the proliferation and invasion of glioma cells in vitro (Choo et al. 2005). In another study, WEHI-164 fibrosarcoma cells were treated with alive T. gondii tachyzoites. This treatment decreased cell proliferation and increased cell death. However, no significant effect was observed when WEHI-164 fibrosarcoma cells were treated with Trichomonas vaginalis trophozoite or Leishmania major promastigote (Shirzad et al. 2012). Trypanosoma cruzi lysates were used to treat human breast cancer cells in vitro. This treatment inhibited the cancer cells growth (Sheklakova et al. 2003). Also, Atayde et al. showed that the T. cruzi surface molecule gp82 could induce cell death and apoptosis in melanoma cells in vitro (Atayde et al. 2008). A recombinant product of T. spiralis induced apoptosis in the human hepatoma cell line (H7402) (Wang et al. 2013). In another work, the human chronic myeloid leukemia cell line (K562) and hepatoma cell line (H7402) were treated with T. spiralis crude antigens in vitro. This treatment induced apoptosis in cancer cells (Wang et al. 2009). Apoptosis was a mechanism of tumor cells caused by A. castellani or its lysates (Alizadeh et al. 1994).

Table 2.

Evidence about anti-cancer effects of parasites in vitro and human population

Parasites or their derivatives	Type of work	Effect	References
Trypanosoma cruzi lysates	In vitro	Inhibition of breast cancer growth	Sheklakova et al. (2003)
Trypanosoma cruzi surface molecule gp82	In vitro	Induce cell death and apoptosis in melanoma cells	Atayde et al. (2008)
Toxoplasma lysate antigen (TLA)	In vitro	Inhibits the proliferation and invasion of glioma cells	Choo et al. (2005)
Toxoplasma gondii tachyzoite	In vitro	Decreased cell proliferation and increased fibrosarcoma cell death	Shirzad et al. (2012)
	In vitro
Rabbit anti-Toxoplasma antibodies	In vitro	React with mouse melanoma or breast cancer cells but not with normal mouse lymphocytes	Mohamadi et al. (2019)
A novel gene product of Trichinella spiralis	In vitro	Antisera against this product cross-reacted with SP2/0 Myeloma cells	Duan et al. (2013)
Trichinella spiralis crude antigens	In vitro	Apoptosis of cancer cells	Wang et al. (2009)
Protoscolices	In vitro	Induce Cell Death in WEHI-164 Fibrosarcoma Cells	Yousofi Darani et al. (2012)
Sera of patients with hydatid diseases	In vitro	Cytotoxic effects on NCI-H209/An1 cells (lung cancer) but not on fibroblast cells	Karadayi et al. (2013)
Anti-HCF antibodies	In vitro	Reacts with antigens on CT26 colon cancer cells	Berriel et al. (2013)
Mucin-like peptides from E. granulosus	In vitro	Activated natural killer (NK) cells increased in the spleens of immunized mice	Noya et al. (2013)
Hydatid cyst fluid	In vitro	Induction of apoptosis on breast cancer cells	Daneshpour et al. (2019)
Strongyloides stercoralis	Human population	Mean survival of patients with leukemia who were simultaneously infected with Strongyloides stercoralis was longer than the mean survival of the same patients without this parasitic infection	Plumelle et al. (1997)
Echinococcus granulosous (hydatid cyst)	Human population	The incidence of hydatid cysts in cancer patients was significantly lower than the incidence in a normal population	Akgül et al. (2003)
Toxoplasma gondii	Human population	The low titer of anti-toxoplasma antibodies in the normal population was significantly more frequent than in cancer patients	Sharafi et al. (2015)
Toxoplasma gondii	Human population	Anti-toxoplasma antibodies detected in sera of 8.3% of cancer patients and 12.3% of normal people	Wang et al. (2015)
Malaria	Human population	There is a negative correlation between malaria incidence and mortality of cancers	Qin et al. (2017)

Mechanisms of the anti-cancer effects of parasites in vitro have not been clarified. But, inhibition of cell proliferation, induction of apoptosis, and direct toxicity may be involved. In this regard, it has been shown that T. spiralis has a powerful cytotoxic effect on different cancer cells (Pocock and Meerovitch 1982). In another study, NCI-H209/An1 human lung small carcinoma cells and L929 mouse fibroblasts were treated with a serum of patients diagnosed with hydatid disease or sera of patients without a history of hydatid disease. Sera of patients with hydatid diseases had cytotoxic effects on NCI-H209/An1 cells, but they did not have cytotoxic effects on normal fibroblast cells. Sera of healthy subjects did not have any cytotoxic effect on the tumor cell line or control fibroblasts (Karadayi et al. 2013).

Induction of apoptosis is another mechanism of the anti-cancer effect of parasites in vitro. It has been shown that parasites or their molecules can induce apoptosis and cell death in various cancer cells (Atayde et al. 2008; Shirzad et al. 2012; Wang et al. 2009; Yousofi Darani et al. 2012). Crude extracts of T. spiralis inhibited the growth of five cell lines in vitro, and inducing apoptosis in those cells (Wang et al. 2009). Recently, a research group discovered that a protease inhibitor highly expressed by the oncosphere of E. granulosus (Ranasinghe et al. 2015) could inhibit the growth of several human cancer cells without affecting normal cell growth (Ranasinghe et al. 2018). Some parasite molecules induce apoptosis only on cancer cells but not on normal ones. For example, it has been shown that T. cruzi surface molecule gp82 can induce apoptosis in melanoma cells without affecting normal melanocytes (Atayde et al. 2008). These molecules would be convenient candidates for cancer therapy to target cancer cells without inducing damage to normal cells.

In another type of in vitro study, it has been shown that rabbit anti-Toxoplasma antibodies selectively attach to mouse melanoma or breast cancer cells but not to mouse normal spleen lymphocytes (Mohamadi et al. 2019). In agreement with these observations, it has been shown in another study that anti-T. spiralis antibodies had an obvious cross-immune response with myeloma cell SP2/0 antigens (Gong et al. 2011). Also, antiserum against a novel gene product of T. spiralis cross-reacted with SP2/0 myeloma cells (Duan et al. 2013). Moreover, antibodies against T. cruzi cross‐reacted with human colon and breast cancer cell lines. (Ubillos et al. 2016). These anti-parasites antibodies, which selectively react with cancer cells but not with normal cells, could be candidates for selective cancer therapy in humans.

Evidence about anti-cancer effects of parasites according to in vivo experiments

Most investigations about the anti-cancer effects of parasites in the animal model are either prophylactic or therapeutic works. In the former type, mice were immunized with the parasites and challenged with cancer cells. While in the latter form, the tumor-bearing mice were treated with parasites and then monitored for the progression of tumor growth (Fig. 1). Anti-cancer effects of T. cruzi have been burnt up since a long time ago when scientists from Solvent Union reported that T. cruzi inhibits cancer growth (Oliveira et al. 2001). They believed that the induction of a protective immune response against cancers and/or secretion of toxic substances are mechanisms of the anti-cancer effect of this parasite (Kallinikova et al. 2001). It was imagined that the Cold War competition between the superpowers during the second half of the twentieth century played an essential role in shaping this research idea (Krementsov 2009). However, in recent decades there has been scientific evidence about the anti-cancer effect of this parasite.

Fig. 1.

Two main types of investigations about anti-cancer effects of parasites (A), Mechanisms of anti-tumor effects of parasites in animal models works (B)

Oliveria et al. showed that chronic infection with T. cruzi was associated with a low incidence of chemically induced colon cancer in rats (Oliveira et al. 2001). Another study reported that T. cruzi infection inhibited the growth of sarcoma tumors about 1.5–22 times (Kallinikova et al. 2001). On the other side, immunization with lysates of this parasite resulted in the inhibition of Ehrlich adenocarcinoma (Kallinikova et al. 2006) and melanoma (Alejandra et al. 2014) growth.

The immune response raised against T. cruzi may mainly inhibit cancer growth (Cabral 2000). In agreement with this conception, it has been shown that immunization with extracts of T. cruzi raised a protective cellular and humoral immune response against chemically induced colon and breast cancer animal models. In another work, immunization of mice with share antigens of T. cruzi and Ehrlich adenocarcinoma resulted in oncoprotective effects (Zenina et al. 2008). Zhigunova et al. also showed that the transfer of splenocytes from animals immunized with T. cruzi leads to the inhibition of cancer growth (Zhigunova et al. 2013). Besides immune response, direct effects of the parasite molecules may have a role in the anti-cancer effects of T. cruzi. In this regard, it has been shown that T. cruzi calreticulin (TcCRT) can inhibit angiogenesis and tumor growth (Ramírez et al. 2012). By application of polyclonal anti-rTcCRT F(ab’)2 antibodies, the anti-tumor activity of T. cruzi was neutralized, indicating that rTcCRT is a valid mediator of the anti-cancer effects (Abello-Cáceres et al. 2016). In experiments with T. gondii, it has been shown that injection of live tachyzoites of this parasite resulted in decreasing growth of lung cancers (Kim et al. 2007) and melanoma (Hunter et al. 2001) in mice. Anti-cancer effects of extracts of killed Toxoplasma tachyzoites have also been investigated in different works. Results of these researches showed that immunization with this parasite resulted in reduced growth of fibrosarcoma (Darani et al. 2009), melanoma (Jiao et al. 2011), lymphoma (Suzuki et al. 1986) and chemically induced (Miyahara et al. 1992) tumors in mice.

One of the main limitations and disadvantages of all the above in vivo studies with T. gondii is that they had not been designed to evaluate the therapeutic effects of Toxoplasma against established tumors. The other limitation of using live Toxoplasma for cancer therapy is that cancer patients are immunocompromised, and Toxoplasma can replicate and disseminate quickly in such patients. So, a mutant nonreplicating uracil auxotroph strain (cps strain) of the parasite has been developed (Fox and Bzik 2002). This parasite strain invades host cells but does not replicate in them. Vaccination of mice with cps strain resulted in the generation of CD8 T cells immunity which may be against not only the Toxoplasma parasite but also against other pathogens or tumors (Gigley et al. 2009). Toxoplasma cps strain has been used to treat tumors in animal models (Fox et al. 2013). In an investigation, murine melanoma was treated with a cps strain of the parasite. This treatment leads to the regression of the established tumor (Baird et al. 2013a). In another study, treating mice with ovarian cancer with cps resulted in substantial therapeutic benefits (Baird et al. 2013b).

With Plasmodium spp., malaria-causing parasites, Chen et al. showed that malaria infection significantly suppresses Lewis lung cancer growth in a murine model. This anti-cancer action of the parasite was due to the induction of innate and adaptive anti-tumor responses (Chen et al. 2011). There are more works to support this idea that the anti-cancer effects of plasmodium are immune-dependent. Immunization with genetically attenuated sporozoites (GAS) resulted in the inhibition of Lewis lung cancer growth and angiogenesis and induction of anti-tumor immune responses (Deng et al. 2016). Also, the anti-leukemia activity of P. yoelii infection in mice was tested and showed that malaria parasite infection significantly decreased WEHI-3 leukemia cell proliferation. This infection induced anti-leukemia by promoting immune responses in mice (Tong et al. 2018).

It has been shown that myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) increase significantly in hosts with advanced malignancies and have a suppressive effect on anti-cancer activities of the immune system (Curiel 2007; Restifo 2007). Plasmodium substantially reduces the proportions of Tregs and MDSCs cells in the lung tumor tissues and increases CD8⁺ T cell-mediated cytotoxicity in the tumor microenvironment (Adah et al. 2019). Also, with the aim of cancer immunotherapy, Plasmodium parasites have been utilized as vectors to express tumor-associated antigens (Liu et al. 2017).

In a different non-immunological-based work, exosomes (bilayer lipid membrane vesicles containing various macromolecules) derived from the plasma of Plasmodium-infected mice were collected and used for intra-Lewis lung tumor injection. This treatment significantly reduced Lewis lung cancer growth in mice (Yang et al. 2017). It has been shown that the VAR2CSA protein from Plasmodium falciparum selectively attaches to cancer tissues, not normal ones. This protein can selectively target cancer cells in cancer therapy (Salanti et al. 2015). Acanthamoeba castellani or its lysates resulted in 83% and 53% reduction of tumor growth progression, in murine melanoma, respectively (Pidherney et al. 1993).

Besides protozoan parasites, the anti-cancer effects of some helminths have also been reported. In experiments with E. granulosus larval stage (Hydatid cyst), animals in case groups were vaccinated with protoscolices (Chookami et al. 2016) or hydatid cyst fluid (Berriel et al. 2013). Control groups were injected with isotonic saline or left intact without vaccination. After that, all mice were injected with cancer cells. The tumor size growth in vaccinated mice was significantly less than in the control mice. In another experiment, mice were first immunized with hydatid cyst wall antigens and then challenged with 4T1 breast cancer cells. Significant inhibition of 4 T1 breast tumor growth, a decrease in metastasis, and longer survival time were observed in the immunized mice (Shakibapour et al. 2021).

Although the results of these types of studies are interesting, they cannot be translated into human cancer therapy directly. So in another set of work, mice were firstly challenged with melanoma (Rostami et al. 2018) or colon (Berriel et al. 2013) cancer cells and then were treated with hydatid cyst fluid or its 78 kDa fraction. Control mice were left intact without treatment. Again, the size of tumor in the treated mice was significantly less than the size of tumor in control mice. According to the results of these works, it is possible to design clinical trial investigations for treatment of human cancer.

In most investigations about the anti-cancer effects of parasites in animal models, tumors were grafted to mice by injection of cancer cells. Another way of developing cancer in animals is injection of certain chemicals. For example, Altun et al. injected live protoscolices intraperitoneally into one group of rats (case group) and control group was left intact without infection. All rats in case and control groups were injected with dimethyl benzanthracene (DMBA) to induce breast cancer. The results showed that hydatid cyst infection prevented the tumorigenesis caused by DMBA by 50% (Altun et al. 2015). Opposite to the anti-cancer effects of hydatid cyst results, co-existence of echinococcosis and metastatic lesions in the liver of mice was observed; these metastatic lesions were associated with a significant reduction in the IFN-gamma and Th1 cells (Turhan et al. 2015).

Anti-cancer effects of T. spiralis have been recently reviewed (Liao et al. 2018). In rats, T. spiralis infection inhibits mammary gland cancer induced by 7,12-dimethylbenzo (a) anthracene (Apanasevich and Britov 2002). In another study, mice were orally infected with T. spiralis and then challenged with B16-F10 melanoma cells. Infection with the parasite caused a significant reduction in tumor growth and lung metastasis (Kang et al. 2013). In another work, an inhibitory effect of S. mansoni antigen on the progression of chemically induced colon carcinogenesis has been reported (Eissa et al. 2019). In a study, mice were immunized with sonicated Toxocara canis eggs mixed with alum as an immune adjuvant to form treatment groups. Control mice were injected with alum alone. All mice were then challenged with WEHI164 Fibrosarcoma cells. There was a significant reduction in tumor growth in T. canis immunized mice (Darani et al. 2009). Evidence about the anti-cancer effects of parasites in animal model works has been summarized in Table 3.

Table 3.

Evidence about anti-cancer effects of parasites in animal model works

Parasites	Anti-tumor effect	References
Infection with Trypanosoma cruzi	Low incidence of chemically induced colon cancer in rats	Oliveira et al. (2001)
Immune response against Trypanosoma cruzi	Inhibit cancer growth	Cabral (2000)
Extracts of Trypanosoma cruzi	Protective immune response against colon and breast cancers	Ubillos et al. (2016)
Trypanosoma cruzi calreticulin (TcCRT)	Inhibit angiogenesis and tumor growth	Ramírez et al. (2012)
Lysates of Trypanosoma cruzi	Inhibited growth of Ehrlich adenocarcinoma	Batmonkh et al. (2006)
Cell transfer of animals immunized with Trypanosoma cruzi	Inhibition of cancer growth	Zhigunova et al. (2013)
immunization by Trypanosoma cruzi	Reduction of the size of tumors	Kallinikova et al. (2006), Alejandra et al. (2014)
Live Toxoplasma	Decrease growth of different tumors	Hunter et al. (2001), Kim et al. (2007)
Nonreplicating uracil auxotroph strain of Toxoplasma (cps strain)	Decrease growth of tumor of melanoma or ovarian bearing mice following treatment with cps	Baird et al. (2013a), Baird et al. (2013b)
Extracts of dead Toxoplasma tachyzoites	Decrease growth of different tumors	Miyahara et al. (1992), Jiao et al. (2011), Darani et al. (2009), Suzuki et al. (1986)
Immunization with genetically attenuated sporozoites	Inhibition of lung cancer growth and angiogenesis	Deng et al. (2016)
Malaria infection	Decreased WEHI-3 leukemia cell proliferation	Tong et al. (2018)
Exosomes derived from the plasma of Plasmodium-infected mice	reduction of Lewis lung cancer growth in mice	Yang et al. (2017)
Injection of plasmodium-infected red blood cells	Reduction of Tregs and MDSCs cells in the lung tumor tissues of the treated mice and also the elevation of CD8+T cells	Adah et al. (2019)
Protoscolices	Reduced the size of melanoma in C57 black mice	Chookami et al. (2016), Altun et al. (2015)
Hydatid fluid or its 78KDa fraction	Reduced the size of Melanoma cancer in Balbc mice	Rostami et al. (2018), Chookami et al. (2016)
Treatment with Hydatid cyst fluid	Protection against tumor formation	Berriel et al. (2013)
Trichinella spiralis infection	Inhibition of mammary gland cancer	Apanasevich and Britov (2002), Kang et al. (2013)

Possible mechanisms of anti-cancer effects of parasites in vivo

The underlying mechanisms of the anti-cancer effects induced by parasites in an animal model have not been well clarified, and little is known in this regard. However, several potential mechanisms have been proposed, including anti-cancer effects through activation of the host immune response, direct anti-cancer or toxic effects induced by parasites, and inhibition of angiogenesis (Fig. 1). The primary mechanism is that induction of anti-cancer effects of parasites is mediated by activation of the host immune system. There is much evidence in the experimental investigations to support the idea that parasites' immune response can interfere with tumor growth. In favor of this hypothesis, antigen similarity between specific cancer and several parasites has been reported (Darani and Yousefi 2012). Previous works have shown that parasites' innate and adaptive immunity activation can cause significant anti-tumor immune responses (Ubillos et al. 2016; Zenina et al. 2008; Zhigunova et al. 2013). In cancer immunology, it has been shown that the Th1 polarized response is essential in killing cancer cells and inhibiting tumor growth, whereas the Th2 polarized response helps tumor progression and metastasis (Zamarron and Chen 2011). It has been shown that T. gondii with anti-cancer activities elicits a strong Th1 polarized response in their hosts (Fox et al. 2013). In agreement with these results, it has been shown that reduced Th1 immune responses in hydatid cyst patients were associated with increased metastatic colony formation in the liver (Turhan et al. 2015). In another work, it has been shown that malaria infection suppresses Lewis lung cancer growth via induction of anti-tumor responses with heightened production of Th1-type cytokines (Chen et al. 2011). Increasing cytolytic activity of CD8+ T cells, secretion of interferon γ (IFN-γ), interleukin-6/12 (IL-6/12), and tumor necrosis factor α (TNF-α) was due to immunization with malaria sporozoites (Deng et al. 2016). Also, it has been shown that the immune response elicited by T. cruzi lysates stimulates the activation of specific CD41 and CD81 T cells with anti-tumor activities (Ubillos et al. 2016).

In contrast with the above evidence, T. spiralis, with anti-cancer activities, triggers a Th2 immune response. So this parasite may induce its anti-cancer effects via activation, differentiation, and proliferation of macrophages and NK cells (Liao et al. 2018). Trichinella spiralis also causes eosinophilia in the host and eosinophils tumoricidal activity has been shown for several tumors (Legrand et al. 2010). So, T. spiralis may cause anti-tumor activities by induction of a high level of eosinophilia.

There is some evidences about the role of humoral immunity in the anti-cancer effects of parasites. It has been found that immunization with T. cruzi lysate developed antibodies specific for colon and mammary rat cancer cells. These antibodies could mediate antibody-dependent cellular cytotoxicity (ADCC) in vitro. Cross-reaction of Anti-T. cruzi antibodies with human colon and breast cancer cell lines have also been shown (Ubillos et al. 2016). In another work, mice immunized with hydatid cyst fluid developed antibodies recognizing tumor cells (Berriel et al. 2013). IgE, which is a critical player in protecting against parasites, may also show anti-cancer activities (Karagiannis et al. 2007).

Cross-reaction of breast cancer patient sera with hydatid cyst wall antigens has also been reported. Mass spectrometry analysis revealed that the cross-reactive antigens of hydatid cyst wall had proteins with a high degree of homology with cancer cells antigens (Shakibapour et al. 2021).

Besides adaptive immunity, innate immunity stimulated by certain parasites may have a role in the anti-cancer effects of parasites. A significant increase in natural killer (NK) cells following some parasitic infections have been noted (Noya et al. 2013). NK cells are the first line of defense against tumorigenesis and play a meaningful role in inhibiting the proliferation and metastasis of tumors (Hansson et al. 1979).

The toxic effects of parasite molecules are another mechanism that parasites may induce their anti-cancer activities. In favor of this theory, it has been shown that Caveolin-1 (cav-1), a plasma membrane protein, which is a tumor suppressor by inducing cell cycle arrest and apoptosis during the early stages of some tumors, has been cloned from T. spiralis adult worm. Also, heat shock proteins (HSPs) which play a significant role in cell growth, differentiation, and survival, have been isolated from T. spiralis (Liao et al. 2018). In another work, T. cruzi (nTcCRT) was identified as responsible for the anti-tumor effect during infection with this parasite (Abello-Cáceres et al. 2016).

Inhibition of angiogenesis is another mechanism of the anti-cancer effects of parasites. Angiogenesis is essential for tumor survival, growth, and progression (Hicklin and Ellis 2005). Immunization with genetically attenuated malaria sporozoites has been shown to inhibit angiogenesis (Deng et al. 2016). In another work, exosomes from Plasmodium-infected hosts suppressed tumor angiogenesis in vivo (Yang et al. 2017).

Evidence about anti-cancer effects of parasites in the human population

In the past, parasites used to be more prevalent than now, and intestinal nematode worms were historically common in most parts of the world. Stoll in 1974 showed that intestinal parasites were among the most common human infections (Stoll 1947). However, parasitic infections are usually more prevalent in poor communities with inadequate sanitation (Alemu et al. 2011). During the last decades, there has been a sharp decline in soil-transmitted helminths (STH) prevalence due to socioeconomic improvement in developed countries (Pullan et al. 2014). So, parasites are usually less common in developed countries and more frequent in underdeveloped and poor communities (Fig. 2).

Fig. 2.

A Relationship between intensity of poverty in 94 countries (X axis) and mean prevalence of hookworms (Y axis), B Relationship between human development index (HDI) (X axis) and incidence of all cancers (Y axis), C Trend of Ascaris egg positive rate in South Korea (Y axis) during 1971–1992 (X axis) and D Trend of age standardized incidence of breast cancer in South Korea (Y axis) during 1999–2015 (X axis)

In contrast to parasitic diseases, cancers are usually more prevalent in developed countries, and there is evidence indicating that cancer incidence increased in western developed countries (Rastogi et al. 2007). It has been shown that in recent years growing incidence of cancer has been associated with socioeconomic development (Bray et al. 2018), and there is a direct relationship between the human development index (HDI) and the incidence of colon cancer (Arnold et al. 2017). With the comparison of the epidemiology of parasitic infections and cancers, it is evident that there is a negative relationship between the distribution of parasitic diseases and cancers. So, wherever parasitic infections have been decreased, cancer incidence increased. As an example, in south Korea following sharp decline of Ascaris lumbericoides prevalence during 1971–1992, there is a remarkable increase in breast cancer incidence during 1992–2013 (Fig. 2). Although many factors may be considered to explain existence of adverse relationship between distribution of parasitic infections and cancers, but there are plenty of scientific evidences indicating that some parasites have anti-cancer effects. So, we have already proposed that parasites may be considered targets for cancer immunotherapy (Darani and Yousefi 2012).

The hygiene hypothesis was postulated to explain higher number of autoimmune diseases in developed countries (Ngoi et al. 2011). This hypothesis was then restated to explain the adverse relationship between the distribution of cancers and microbial infections (Rook and Dalgleish 2011). In support of the hygiene hypothesis, there is some evidence in the human population about anti-cancer effects of parasites. In an investigation, Plumelle et al. showed that the mean survival time of patients with adult T-cell leukemia who were simultaneously infected with Strongyloides stercoralis was longer than the mean survival of the same patients without infection (Plumelle et al. 1997). Also, Akgül et al. showed that among 2086 patients who had surgery for various solid tumors, hydatid cyst was detected in only two patients, while among 350 trauma patients who had surgery, seven patients (2%) with hydatid cyst infections were detected (Akgül et al. 2003). Also, among 1000 patients with hydatid cysts, only one patient was found to have esophageal carcinoma (Altun et al. 2015). In another work, it has been shown that previous infection with Toxoplasma (presence of low titer of antibodies against Toxoplasma) may be associated with resistance to cancer development (Sharafi et al. 2015). It has also been shown that while 12.3% of the normal population of China was seropositive for Toxoplasma (Xiao et al. 2010), 8.3% of patients with cancer in this country showed positive antibodies against Toxoplasma (Wang et al. 2015). Qin et al. investigated the relationship between malaria incidence and cancer mortality in 56 different countries. They showed a negative correlation between malaria incidence and cancer mortality (Qin et al. 2017).

In contrast to the evidence mentioned above about anti-cancer effects of parasites, many reports also show that parasites such as Clonorchis sinensis, Opisthorchis viverrini, Schistosoma haematobium, and Trichomonas vaginalis may involve in etiology of cancers (Machicado and Marcos 2016; Sutcliffe et al. 2012). To solve this paradox, we have already hypnotized that when parasites run a low-density and chronic infection associated with very little damage and usually no symptoms, they may favor the host and show anti-cancer activities. However, when they are in a high-density or acute infection associated with pathologic changes and symptoms of varying degrees, they may be involved in the etiology of different cancers (Darani and Yousefi 2012). Epidemiological data shows that in a normal human population, the majority (85%) of individuals infected with parasites have a low-intensity infection. In contrast, a minor portion (15%) has a high intensity of infection. So, parasites with less or no damage may be candidates for cancer therapy. Evidence about anti-cancer effects of parasites in humans has been summarized in Table 2.

Conclusion and future prospective

Cancers are one of the leading human causes of death; parasites or their antigens may serve as a therapeutic strategy for cancer therapy. Parasites causing no or less damage may be good candidates for this purpose. However, the best option would be recognizing molecules of parasites with anti-cancer activities. These molecules may be more acceptable to be used in humans. For example, we recently found that a 78 kDa fraction of hydatid cyst fluid has significant anti-tumor effects in treating melanoma cancer in an animal model. This fraction could be a convenient candidate to be used in human clinical trials works in the future (Rostami et al. 2018). The application of mass spectrometry technique and bioinformatics analysis is highly recommended to recognize more onco-protective antigens with parasitic origin. Another option for future work would be using an attenuated non-pathogen form of parasites to treat human cancers. In this regard, nonreplicating uracil auxotroph strain of Toxoplasma (cps strain) has provided promising results. Some anti-parasites antibodies react selectively with cancer cells without no or less reaction with normal cells. So, with further work, it is possible to use specific anti-parasites antibodies for selective cancer immunotherapy in humans. Finally, searching for parasite molecules that induce cell death or apoptosis only in cancer cells but not in normal cells would be worthwhile.

Concluding remarks

1. There are much scientific evidence about anti-cancer effects of different parasites in human population, animal model works, or laboratory research.

2. Anti-cancer effects of parasites may be directly induced by the parasites or indirectly achieved due to immune responses raised by them.

3. Parasitic molecules, which are usually strong immunogens and has share epitopes with cancer antigens, are good candidates for human cancer immunotherapy. These antigens may compensate poor immunogenicity of cancer-derived antigens.

4. Using attenuated nonpathogenic forms of parasites or parasite molecules which induce apoptosis or cell death selectively on cancer cells without any damage to normal cells are another option for treatment of cancer in humans.

Author contributions

1. MY MEA and HYD wrote the main manuscript text 2.  HYD had the role of supervising the article 3. MH, AD and ZF prepared figures and edited the article. All authors reviewed the manuscript.

Funding

This work was supported by grant from Isfahn university of medical sciences.

Declarations

Conflict of interest

The authors clarify that there is no conflict of interest.