ONCOLOGY REPORTS 47: 14, 2022

β‑glucan vaccine adjuvant approach for cancer treatment
through immune enhancement (B‑VACCIEN) in specificimmunocompromised populations (Review)
NOBUNAO IKEWAKI1,2, VIDYASAGAR DEVAPRASAD DEDEEPIYA3,
KADALRAJA RAGHAVAN4, KOSAGI‑SHARAF RAO5, SURYAPRAKASH VADDI6,
HIROSHI OSAWA7, TOMOHIKO KISAKA8, GENE KUROSAWA9, SUBRAMANIAM SRINIVASAN3,SEYDUNGANALLU RAMASAMY BALAGANESA KUMAR10, RAJAPPA SENTHILKUMAR11,
MASARU IWASAKI12, SENTHILKUMAR PREETHY11 and SAMUEL J.K. ABRAHAM3,12‑15
1Department of Medical Life Science, Kyushu University of Health and Welfare; 2Institute of Immunology,
Junsei Educational Institution, Nobeoka, Miyazaki 882‑8508, Japan; 3The Mary‑Yoshio Translational Hexagon (MYTH),
Nichi‑In Centre for Regenerative Medicine (NCRM), Chennai 600034; 4Department of Paediatric Neurology,
Kenmax Medical Service Private Limited, Tallakulam, Madurai 625002, India; 5Institute of Scientific Research andHigh Technology Services of Panama (INDICASAT‑AIP), Clayton 88888, Republic of Panama; 6Department of Urology,
Yashoda Hospitals, Hyderabad, Telangana 50008, India; 7Clinical Services Department, Omote Medical Clinic,
Chiba 296‑8602; 8Division of Biodesign, Office of Research and Academic‑Government‑Community Collaboration,
Hiroshima University, Higashihiroshima, Hiroshima 739‑8511; 9Department of Academic Research Support Promotion Facility,
Center for Research Promotion and Support, Fujita Health University, Toyoake, Aichi 470‑1192, Japan;
10
Department of Sociology, Manonmaniyam Sundaranar University, Abishekapatti, Tamil Nadu 627012;
11
The Fujio‑Eiji Academic Terrain (FEAT), Nichi‑In Centre for Regenerative Medicine (NCRM), Chennai 600034, India;
12
Centre for Advancing Clinical Research (CACR), University of Yamanashi‑ School of Medicine, Chuo, Yamanashi 409‑3898;
13
Edogawa Evolutionary Laboratory of Science (EELS), Edogawa Hospital; 14Japan JBM Inc., Tokyo 133‑0052;
15
Antony‑Xavier Interdisciplinary Scholastics (AXIS), GN Corporation Co. Ltd., Kofu, Yamanashi 400‑0866, Japan
Received June 2, 2021; Accepted October 7, 2021
DOI: 10.3892/or.2021.8225
Abstract. The incidence of cancer, which is the second leading
cause of mortality globally, continues to increase, althoughcontinued efforts are being made to identify effective treat‑ments with fewer side‑effects. Previous studies have reported
that chronic microinflammation, which occurs in diseases,
including diabetes, along with weakened immune systems,
may ultimately lead to cancer development. Chemotherapy,
radiotherapy and surgery are the mainstream approaches to treat‑
ment; however, they all lead to immune system weakness, which
in turn increases the metastatic spread. The aim of the present
review was to provide evidence of a biological response modifier
β‑glucan [β‑glucan vaccine adjuvant approach to treating cancer
via immune enhancement (B‑VACCIEN)] and its beneficial

Correspondence to: Dr Samuel J.K. Abraham, Antony‑Xavier
Interdisciplinary Scholastics (AXIS), GN Corporation Co. Ltd.,
3‑8 Wakamatsu, Chuo, Kofu, Yamanashi 400‑0866, JapanE‑mail: drsam@nichimail.jp

Key words: vaccine adjuvant, β‑glucan, cancer, immune weakness

effects, including vaccine‑adjuvant potential, balancing metabolic
parameters (including blood glucose and lipid levels), increasing
peripheral blood cell cytotoxicity against cancer and alleviating
chemotherapy side effects in animal models. This suggests its
value as a potential strategy to provide long‑term prophylaxis in
immunocompromised individuals or genetically prone to cancer.
Contents
1. Introduction
2.	Vulnerable populations require a continuous implementa‑tion approach for cancer prevention
3. A vaccine therapy approach for cancer treatment
4.	
β‑glucan vaccine adjuvant approach for cancer treatment
through immune enhancement (B‑VACCIEN)
5. Chronic microinflammation, cancer and β‑glucans
6. Conclusion
1. Introduction
Cancer is a lethal disease, responsible for ~9.6 million
deaths annually, thus rendering it the second leading cause

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IKEWAKI et al: B-VACCIEN ADJUVANT TO COMBAT CANCER IN SPECIFIC IMMUNOCOMPROMISED INDIVIDUALS

of mortality globally (1). The most common cancer types
include lung, breast, colorectal, prostate, skin (melanoma)
and stomach cancer. The treatment approach to cancer ismultifactorial, with chemotherapy, radiotherapy and surgery
being the main methods of treatment (1). The immune system
plays a major role in all aspects of cancer, including its origin,development, metastasis, therapy and prevention. Cancer cells
and the immune system are in a constant crosstalk, whereincancer cells undergo three phases: i) Elimination; ii) equilib‑
rium; and iii) escape. In the elimination phase, immune cells,
particularly innate immune cells, are in constant surveillance,
eliminating cells that are abnormal. The elimination process
induces cancer cells to undergo immune‑editing or sculpting,causing an increase in the number of cells that have decreased
immunogenicity and become resistant to the immune
surveillance process; this part is the equilibrium phase. The
cells that become resistant can escape the immune system anddevelop into advanced‑stage cancer (2).
2. Vulnerable populations require a continuous
implementation approach for cancer prevention
It is possible to identify subsets of vulnerable populations who
are at high risk of either developing cancer or who have cancer,
but require intervention for preventing cancer progression.
These populations include:i) Aged individuals with ‘inflammaging’. There is sufficientevidence regarding how age‑related pathologies, including
cancer, cardiovascular diseases and type 2 diabetes, have acommon inflammatory background, involving the processtermed as ‘inflammaging’. In inflammaging, there is a constantsystemic proinflammatory state with increased levels of circu‑
lating ILs, including IL‑6 and IL‑1, as well as TNF‑α andother inflammatory markers. A chronic antigen load caused by
infections, cellular senescence, a dysregulated DNA damage
response, altered gut microbiota, meta‑inflammation and somemicroRNAs (miRNAs/miRs) that are associated with aging
also influence the causative factors for cancer, simultaneously
influencing and aiding inflammaging, thereby leading to cancer
formation and progression (3). Along with increasing age,studies have revealed that there is an enhancement in the numberof natural killer (NK) cell subpopulations, as well as a redis‑
tribution. The re‑distribution is characterized by an increaseof CD56bright cell populations, which are more immature, andof CD56 dim mature cells, with intrinsic, reduced cytotoxic
activity at single‑cell level. Moreover, NK cells from elderly
populations produce less IFN‑γ upon IL‑2 stimulation (4). Thisimmunocompromising nature may also influence the elderly
population in becoming prone to cancer development.
ii) Individuals with genetic risk variants, which are prone
to cancer development either caused by the variants them‑selves or due to negative influences on the immune system (5).
The association between genes and cancer is well known.
For instance, the most commonly mutated gene in all cancer
types is p53. Moreover, inherited mutations in the BRCA1and BRCA2 genes are associated with hereditary breast andovarian cancer syndromes (5). The study by Imai et al (6)examined immune system weakness and cancer development.
Between 1986 and 1990, these authors assessed the natural
cytotoxic activity of peripheral blood mononuclear cells

using an isotope‑release assay in 3,625 residents of a Japanese
population who were mostly aged >40 years. These authors
also conducted an 11‑year follow‑up survey for the cohort
members, aiming to examine cancer incidence and mortality.
The follow‑up results indicated that medium and high cytotoxic
activity of peripheral‑blood lymphocytes was associated with
reduced cancer risk, whereas low activity was associated withincreased cancer risk (6).
iii) Individuals with lifestyle and metabolic disorders:
For >70 years, the association diabetes and cancer has been
hypothesized (7). Epidemiological data have demonstrated
that patients with diabetes are at an increased risk of devel‑
oping various types of cancer, with an increased mortality
rate. Several pathways have been proposed for the association
between diabetes and cancer, including: a) Hyperglycaemia
leading to increased cancer risk via augmented oxidative stressand DNA damage; b) hyperinsulinemia, due to exogenous
insulin or insulin analogues [this view has been challenged
by a previously published study (7)]; and c) chronic microin‑
flammation with cytokine dysregulation (7). Hyperglycaemia
in diabetes generally favours malignant cell proliferation by
providing energy to the cancer cells. Increased levels of chronic
inflammatory markers, including IL‑1β, IL‑6 and TNF‑ α,have been observed in diabetic patients, which may indicate
the activation of the immune response in the progression anddevelopment of cancer cells. The uncontrolled proinflamma‑
tory response environment in diabetes, which is caused bychronic accumulation of glycated biomolecules and advanced
glycation end products, leads to a chronic inflammatory state
induced by the activation of the transcription factor NF‑кB andthe generation of reactive oxygen species (ROS) in cells. These
factors promote a tumour‑favourable microenvironment andpotentially trigger immune system overactivation, ultimately
leading to cancer growth (8,9). With regards to metabolic
syndromes, chronic inflammation and cancer, a chronic andstable background inflammation has been proposed, referred
to as a ‘hypothalamic microinflammation’ (9). This is causedby the hypothalamus atypically undergoing proinflamma‑
tory signalling activation, occurring alongside increases
in age and the development of metabolic syndrome. Thishypothalamic microinflammation has also been reported toprogrammatically control whole‑body aging. Since aging is
also associated with a chronic inflammatory state, negatively
associated with longevity but positively with neurodegenera‑tive diseases, an association between the hypothalamus anda microinflammatory state leading to cancer has become
increasingly evident (10).
iv) Individuals with immune system weaknesses due toa) aged individuals with inflammaging; b) individuals withgenetic risk variants; and c) individuals with lifestyle andmetabolic disorders.
v) Patients with cancer undergoing chemotherapy, radio‑
therapy or surgery, which lead to therapy‑induced immune
dysfunction (11‑13). Chemotherapy or a chemo‑ and radio‑
therapy combination have been reported to significantly
delay the immune recovery to pre‑treatment baseline levels.
Similarly, surgery leads to a window of opportunity that allows
the residual cancer cells, including those that have undergone
distant metastases, to gain a foothold in the absence of NK cellsurveillance (12).

ONCOLOGY REPORTS 47: 14, 2022

Since conventional therapies have an associated riskof therapy‑induced immune dysfunction, it is important to
identify an approach that is effective in the long term as an
adjunct to the other interventions, which would help maintainthe normal function of the immune system, thereby enhancing
its immune surveillance and antitumour properties, andultimately playing a potential role in cancer prevention.
3. A vaccine therapy approach for cancer treatment
According to the Centers for Disease Control and Prevention
in the USA, a vaccine is a product that stimulates the immune
system of an individual to produce immunity against a specificdisease (14). Vaccines in cancer may be therapeutic or preventive.
Preventive cancer vaccines include proteins, peptides, DNA or
RNA that can elicit or boost pre‑existing antitumour immunity,
leading to cancer elimination and the production of long‑term
memory to prevent tumour recurrence (15). The purpose of atherapeutic cancer vaccine is to control the cancer burden.
Such vaccines include autologous patient‑derived immune
cell vaccines, tumour antigen‑expressing recombinant virus
vaccines, peptide vaccines, DNA vaccines and heterologous
whole‑cell vaccines derived from established human tumour celllines (16). The personalized dendritic cell vaccine sipuleucel‑T(Provenge) and recombinant viral prostate cancer vaccine
PSA‑TRICOM (Prostvac‑VF) are widely known vaccines in the
pre‑approval/authorized approval/late clinical trial stages (17).
Vaccines are often administered with adjuvants, which help toimprove poorly immunogenic vaccines (18). Different types ofnovel adjuvants have been identified and applied with cancer
vaccines, which include inorganic nanoparticles, organic mole‑cules and polymers (19). Pathogens stimulate a ‘danger sensing’
signal via pathogen‑associated molecular patterns (PAMPs).
Inorganic nanoparticle‑based adjuvants function in a similarmanner to PAMPs, thereby stimulating antitumour immunity.
Organic molecule‑based adjuvants include small molecule‑based
factors, such as modified PAMPs, and are novel ligands forpattern recognition receptors (PRRs). Agonists of the Toll‑likereceptor family, which are type I transmembrane proteins that
regulate the innate and adaptive immune responses (19), andagonists of stimulator of IFN genes (20) are examples of organic
adjuvants. Polymer‑based adjuvants concurrently help in drugdelivery and act as PAMPs for immune system activation. At
present, alum (a mixture of diverse aluminium salts) has been the
only approved adjuvant in humans and remains one of the mostcommon adjuvants in human vaccines. In addition to aluminium
salts, oil‑in‑water emulsions containing squalene (e.g., MF59
and AS03), in vitro‑assembled influenza‑virus‑like particles(e.g., virosomes) and the liposome‑based adjuvant system AS01,
are other licensed adjuvants in human vaccines (21).
However, it remains unknown whether there is a nutrition‑­based supplementation that can act as a potential vaccine
adjuvant to facilitate cancer treatment, which can be bothpreventive and therapeutic.
4. β‑glucan vaccine adjuvant approach for cancer treatment
through immune enhancement (B‑VACCIEN)
β ‑glucans, as a result of their high biocompatibility andtolerability and satisfactory safety profile, possess numerous

3

beneficial properties, establishing them as promising adjuvant
candidates (21‑23). Dietary phytochemical carbohydrates havebeen considered as effective cancer‑preventing and therapeutic
adjuvants, which can be supplemented continuously for a longer
time period (24). Among such phytochemicals, saponins andβ‑glucans are widely distributed in the plant kingdom, and intheir purified extract form, represent two of the most potent
immunological adjuvants when injected as a mixture with
antigen, or immunomodulators when orally ingested (25).
β ‑glucans are naturally occurring polysaccharides thatare constituents of the cell walls of yeast, fungi (including
mushrooms), some bacteria, seaweed and cereals (oat andbarley) (26). β ‑glucans are functional bioactive compounds
possessing hypocholesterolaemic, hypoglycaemic, immuno‑
modulatory, antitumor, antioxidant and anti‑inflammatory
activities. Moreover, their macromolecular structure and func‑
tionality vary, depending on the source (27). Yeast‑derived
1,3‑1,6 β‑glucans have been reported to exert more prominent
biological response modifier (BRM) effects compared with
β ‑glucans from other sources, including oats or barley (28).
An immunomodulator includes any molecule or substancecapable of interacting with the immune system, resulting
in the up‑ or downregulation of specific components of theimmune response (29). Immunomodulators comprise of anarray of synthetic, natural and recombinant molecules. Natural
molecules, including those found in curcumin, thyme, bayleaf, resveratrol, ginseng, echinacea, aloe vera, astragalus,
goldenseal, flavonoids and essential oils, have been studied
for their immunomodulation properties as nutritional supple‑
ments. However, direct comparison studies of individual
immunomodulators are limited. Vetvicka et al (26) indicatedthat, amongst >20,000 published studies, compared with otherimmunomodulators, glucan was the most prominent one.
Glucans are BRMs that exert significant effects on various
components of the immune system. Glucans are recognizedby PRRs present on the membranes of immune cells, such as
macrophages, monocytes, dendritic cells and NK cells, with
their key receptors being Dectin‑1 and complement receptor 3(CR3; CD11b/CD18). Additional receptors include Toll‑2,
lactosylceramides and the scavenger receptor family (26).
In terms of cancer immunity, β‑glucans have been demon‑
strated to possess various functions, including: i) the increaseof infection resistance (which is of particular importance invirus‑associated cancer types); ii) exerting antitumour effects
by activating the adaptive and innate arms of the immune
system; iii) stimulating immune cells, including leukocytes,
T helper (Th) and NK cells; and v) exerting anticoagulant
effects (30). β ‑glucans activate early innate reactions byacting as PAMPs. Glucan‑activated B cells have been revealed
to secrete proinflammatory lymphokines, including IL‑8,
through the involvement of several molecules including
Dectin‑1 receptors, MAPK and NF‑κ B and activator protein‑1transcription factors. β‑glucans have also been demonstrated to
be potent cellular immunity activators. The effects of β‑glucan
against various types of infection have been demonstrated, suchas for example Leishmania (L.) major, Leishmania donovani,
Candida albicans, Toxoplasma gondii, Streptococcus suis,
Plasmodium berghei, Staphylococcus aureus, Escherichia coli,
Mesocestoides corti, Trypanosoma cruzi, Eimeria vermiformis
and Bacillus anthracis (26).

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The antitumour effects of β‑glucans against a wide varietyof tumour types (26). The mechanism of the antitumor activity
induced by β‑glucans is proposed to occur via the enhance‑
ment of the immune system against tumour cells, as well as
by inhibiting tumour invasion and progression via a complex
modulation of the apoptotic and angiogenic mechanisms. The
antitumour mechanisms enhanced by β‑glucans involve several
pathways. For instance, β‑glucans bind with specific receptors,
such as Dectin‑1, expressed on myeloid cells, converting theminto antigen presenting cells. This binding also activates CD4+
and CD8+ T‑cells, which are stimulated to produce the proin‑
flammatory cytokine, TNF‑α, the antitumor cytokine, IFN‑γ,
granzyme B and perforins, all of them cytotoxic against
cancer cells (31). The tumoricidal effects are also induced byswitching suppressive M2 macrophages into inflammatory M1
macrophages and, in turn, activating Th1‑type T cells, thereby
enabling cancer cell destruction via the secretion of proinflam‑
matory cytokines through these T‑cells. Interactions between
β‑glucan and polymorphonuclear cells induce the release of
ROS in the microenvironment, ultimately leading to tumour
cell death. β ‑glucans also activate NK cell cytotoxicity via
the production and release of proinflammatory cytokines andvia complement activation (31). β‑glucans have been demon‑
strated to effectively modify the tumour microenvironment,
resulting in significant reduction of primary tumour growthand distant metastases (31). β‑glucans have a strong synergy
with antibodies (Abs) that naturally occur in cancer (26).
β ‑glucans as adjuvants. Japan is a forerunner on the useof β ‑glucans, and β ‑glucans from the Shiitake mushroom(lentinan) and Coriolus versicolor (polysaccharide‑K) havebeen licensed drugs since 1983. As of 2019, 177 clinical trials
valuating β ‑glucans have been listed in the United States
database, ClinicalTrials.gov, for cancer, cholesterol‑lowering
effects and immune‑modulation (26). Clinical trials on
β ‑glucans in combination with the other cancer therapies,
including monoclonal Abs (mAbs), have been reported
mentioned in the review article by Vetvicka et al (26), revealing
significant tumour regression, a favourable Ab response,
elevated immune cell number and function, fewer side‑effects,
decreased cancer‑related fatigue and an improved nutritional
state (26). Thus, β ‑glucans can serve as potential adjuvants
with other cancer treatments.
β ‑glucans are potential adjuvants that aid immuno‑
modulation, in combination as well as when administeredalone (32). Since glucan receptors, including Dectin‑1, CR3,
lactosylceramide, natural cytotoxicity receptor p30 andscavenger receptors, are expressed on different types of
immune cells, including macrophages, NK cells and neutro‑
phils, β‑glucans have a distinct affinity with these receptors,
according to their different chemical structure. Thus, they arecapable of triggering different host responses, making thempotential immune adjuvants. β‑glucan particles derived from
Saccharomyces cerevisiae cell walls have also been suggested
to be used as vaccine adjuvant carriers for protein antigen
delivery, and for the targeted delivery of compounds to macro‑phages and dendritic cells (33). β‑glucans have been reported
as trained immunity‑based adjuvants for rabies vaccines andhave been demonstrated to elicit B‑cell and T‑cell specificresponses in a study on canines (34).

With regards to adjuvant immunotherapy for cancer, sinceboth dendritic cell priming and check‑point inhibitor blockades
have been revealed to be required for immunotherapy (23),β‑glucans serve as an ideal candidate, as they induce dendritic
cell priming and potentiate Abs against immune checkpoint
molecules (26). β ‑glucans have been used as adjuvants inassociation with chemotherapy in different types of cancer,
including oestrogen receptor‑negative human breast, gastric,colorectal and non‑small‑cell lung cancer, as well as haema‑
tological diseases. The advantages of β‑glucans as effective
anticancer therapy adjuvants include the following: i) They
are non‑immunogenic due to the absence of the protein andpeptide components; ii) they are non‑toxic, as even doses up
to 10 mg/kg have been reported to be well‑tolerated in vivo,
with no adverse effects; and iii) they provide the opportunity
for beneficial structural modifications, due to the presence ofmultiple aldehyde and hydroxyl groups (35).
β‑glucans can serve as effective adjuvants with latest thera‑
pies, including mAb‑based and immune checkpoint targeted
therapies for cancer. Combination therapy using β ‑glucan
and mAbs targeting immune checkpoint molecules, including
programmed cell death protein 1 (PD‑1) and programmed
death‑ligand 1 (PD‑L1), has been investigated in preclinicalmodels with promising antitumour efficacy, as reviewed by
Vetvicka et al (26). Several clinical trials have evaluated theinteraction of glucans with mAbs in humans. β ‑glucan has
been examined in association with pembrolizumab in headand neck cancers, metastatic melanoma and breast cancer
with positive outcomes in terms of safety, tolerability andincreased survival. β‑glucans function via the iC3b‑receptor
CR3 (CD11b/CD18), thereby enhancing leukocyte‑mediatedkilling of tumour cells that are coated with iC3b via naturally
occurring antitumor Abs (36).
Trained innate immunity (TRIM) is the innate immune
system memory induced by modulation of mature myeloid
cells or their bone marrow progenitors. This process helps
mediating the sustained increased responsiveness to secondary
challenges (37,38). It is important to note that β ‑glucans
are effective inducers of TRIM, specifically via epigenetic
reprogramming of the innate immune cells at the level of bonemarrow (central TRIM), as well as peripheral TRIM (37,38).
Vetvicka and Vetvickova (39) reported that highly purified
and active glucans exert significant pleiotropic effects against
cancer.
Cancer cell resistance is an important hurdle in anticancer
therapies. β‑glucans are potential candidates for overcoming
treatment resistance in cancer. This effect has been reported
in treatment‑resistant Lewis lung carcinoma (LL/2) cells,
in which Candida cell wall‑derived‑ β ‑glucan exerted asignificant cytotoxic effect on both the parent cell line andcancer stem cells derived from the parent cell line (40).
5. Chronic microinflammation, cancer and β‑glucans
Accumulating evidence has indicated that chronic inflamma‑tion may lead to cancer development. Underlying infection or
inflammation have been linked to 25% of all cancer cases (41).
Any unresolved inflammation on account of the failure in
the precise control of the immune response can continue todisrupt the cellular microenvironment, leading to alterations

ONCOLOGY REPORTS 47: 14, 2022

in cancer‑related genes and post‑translational modifications in
key cell signalling proteins involved in the cell cycle, DNA
repair and apoptosis (41). The identification of mononuclear
inflammatory cells in close association with areas of hyper‑
plasia and cellular atypia has been demonstrated even at very
early stages of tumour development, further supporting theconcept that inflammation is a major driving force that contrib‑
utes to tumour initiation and/or initial tumour progression.
The upregulation of non‑specific proinflammatory cytokines(IFN‑γ, TNF, IL‑1α/β or IL‑6) by immune cells, such as macro‑phages, mast cells and neutrophils, has been shown to promotetumour development (41). The inflammatory processes elicitedby cancer itself are likely to be involved in their progression.
Inflammation is also the common mechanism of action for
numerous cancer risk factors, including infection, obesity,
tobacco smoking, alcohol consumption, exposure to micropar‑
ticles, dysbiosis and chronic inflammatory diseases, including
pancreatitis and colitis. The administration of certain
anti‑inflammatory drugs, including aspirin, has also beenreported to significantly reduce cancer risk. Thus, preventing
or reversing inflammation has been suggested as a promising
approach to cancer control (42).
Chronic‑microinflammation culminating in cancer like‑wise requires focusing on metabolic disorders, including
diabetes and cancer development. Several pathways have been
proposed for the association between diabetes and cancer,
including: i) hyperglycaemia leading to increased cancer
risk via augmented oxidative stress and DNA damage; andii) hyperinsulinemia, involving chronic microinflammation
with cytokine dysregulation, which both require further
attention. The uncontrolled proinflammatory response envi‑
ronment in diabetes caused by the chronic accumulation ofglycated biomolecules and advanced glycation end products
creates a chronic inflammatory state, via the activation of
the transcription factor NF‑кB and ROS generation in cells.
Thus, a tumour‑favourable microenvironment is promoted
and immune system overactivation is potentially triggered,
thereby leading to cancer growth. Moreover, with regards
to chronic inflammation and cancer, a state of chronic andstable background inflammation has been proposed, known as‘hypothalamic microinflammation’ (10), which occurs when
the hypothalamus atypically undergoes proinflammatory
signalling activation, and is associated with age increase andthe development of metabolic syndrome.
β‑glucans, particularly those that are yeast‑derived, aid in
combatting chronic microinflammation, thereby contributing
to a cancer‑preventive response, alongside their metabolicbalancing activities (43,44), further adding to their effects incancer prevention. A previous study on a yeast‑derived β‑glucan
identified its antioxidant activity via H2O2 scavenging, as wellas its in vivo anti‑inflammatory potential in terms of myelo‑
peroxidase activity and malondialdehyde and nitric oxide level
reduction (45). In another study, the regular intake of β‑glucan
was demonstrated to exert an anti‑inflammatory effect, which
occurred by acting on IL‑6, a pleiotropic cytokine that playsa pivotal role in acute phase responses in the balancing of thepro‑ and anti‑inflammatory pathways (46).
Use of a β ‑glucan vaccine adjuvant approach for cancer
treatment. In the majority of the clinical trials on β‑glucans

5

as a cancer treatment adjuvant an oral route of administra‑tion has been used and also across different age groups, as
reviewed by Vetvicka et al (26), indicating that β‑glucan can beapplied universally as an effective treatment adjuvant (26,39).
Following oral administration, β ‑glucans directly interact
with gastrointestinal mucosa cells and are transferred into thegeneral circulation. Vetvicka et al (26) proposed a process of
β‑glucan internalization after which it rapidly enters into thesystemic circulation. The solubility of β‑glucan is a criticalfactor for oral administration and the speed of transfer acrossthe gut is dependent on the physicochemical characteristics of
glucan (26). In this regard, an AFO‑202 BRM glucan (BRMG)
derived from a black yeast (Aureobasidium pullulans AFO‑202
strain) demonstrates high purity and functionality. AFO‑202
glucan is a water‑soluble β ‑glucan which has been used forhuman consumption for several decades (47) and, as a resultof these characteristics, it can serve as a potential β‑glucan
vaccine adjuvant approach to treating cancer.
AFO‑202 β‑glucan has been revealed to be beneficial inmaintaining blood glucose levels and lipid levels in the normal
range in human studies (43,44), assisting in the prevention of
the metabolic‑micro and chronic inflammation axis that may
ultimately lead to cancer. AFO‑202 β‑glucan has been provento stimulate the production of IL‑8 or soluble Fas (sFas),
although not that of IL‑1β, IL‑6, IFN‑γ, TNF‑α or sFas ligand(sFasL) (47). IL‑8 exerts anti‑inflammatory activity and helps
in T‑cell recruitment, as well as ROS metabolism enhancement.
Moreover, IL‑8 serves as a barrier against invading microor‑ganisms, with airway epithelial release of IL‑8 contributing
to the immune defence of the host by promoting neutrophil
chemotaxis (48). Tumours have been demonstrated to express
FasL and downregulate Fas to escape from host immune
surveillance. Elevated sFasL serum levels are associated withcancer progression (49).
Cytokines, including IL‑1, IL‑4 and IL‑6, secreted byimmune cells in the tumour microenvironment are observedin a wide range of solid tumour types, with the expression of
their receptors by cancer cells aiding in immune evasion (50).
IL‑6 promotes tumour growth, with its elevated serum levels
and expression in tumours being negative prognostic markers
for cancer patient survival (51).
While IFN‑γ has been long considered as a central player
in antitumor immunity, it also has pro‑tumorigenic roles. For
instance, IFN‑γ‑mediated activation of the nonclassical major
histocompatibility complex class Ia genes has been shown to
aid in melanoma cell evasion from cytotoxic T‑lymphocyte(CTL)‑mediated cytolysis, in turn leading to clinical failure ofmelanoma peptide vaccines (52). IFN‑γ is also associated with
the influx of monocytic and granulocytic myeloid‑derived
suppressor cells to the tumour microenvironment, leading to
the suppression of the anticancer T‑cell response. Furthermore,
IFN‑γ‑induced PD‑L1/2 ligands on cancer cells causes theirbinding to their immune inhibitory receptor PD‑1, finallysuppressing T and NK cell immune effector activities, thereby
promoting cancer progression (52).
TNF‑α, primarily secreted by tumour‑associated macro‑phages, initiates chronic inflammation. TNF‑α has a dual role:
wherein it causes tumour cell apoptosis when administeredin high doses, however, long‑term low dose administration
has been revealed to accelerate tumour metastasis in a lung

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cancer cell line (40). TNF‑ α also induces the expression ofangiogenic factors, thereby promoting tumour angiogenesis
and accelerating tumour metastasis via the upregulation oftumour‑associated calcium signal transduction protein‑2 via
the ERK1/2 signalling pathway (40,53).
AFO‑202 β‑glucan, could play a key role in preventing thecytokine imbalance‑induced inflammation caused by chemo‑
therapy or other cancer therapies through the balancing ofanticancer cytokines activation and pro‑tumorigenic cytokines
suppression, thus offering benefits in anticancer preven‑tion and therapeutics (11‑13). It has been reported that theDectin‑1‑based recognition of tumour cells orchestrates innate
immune cell antitumour responses (54). The key receptor
via which AFO‑202 β ‑glucan exerts its biological response
and modifying effects is Dectin‑1 (54), thereby suggesting
its potential use as a β ‑glucan vaccine adjuvant. AFO‑202
β ‑glucan has been shown to aid against infections. For
example, AFO‑202 β‑glucan may enhance immunity against
Leishmania amazonensis and malaria through the increase of
NK cell activity and cellular immunity, extending its applica‑tion potential for the suppression of infection, apart from its
anticancer effects (55). At present, the metabolic balancing
effects of this AFO‑202 β‑glucan (43,44) and its vaccine adju‑
vant effects as a potential effector in enhancing the immune
response to the avian influenza A H5N1 and H5N2 vaccines
have been reported (56). The AFO‑202 β ‑glucan has been
demonstrated to enhance the immune system in animal (57)and human clinical studies (58), increasing the eosinophil andmonocyte counts and decreasing the neutrophil‑to‑lymphocyte
ratio (NLR), through the increase in the lymphocyte‑to‑CRP(LCR) and leukocyte‑to‑CRP (LeCR) ratios. Another strainof the Aureobasidium pullulans, N‑163 derived β ‑glucan
has been demonstrated to attenuate lipotoxicity (decrease innon‑esterified fatty acids (NEFA) (59) with anti‑inflammatory
effects of significant control of IL6, D‑Dimer and NLR apartfrom anti‑fibrotic effects in animal (60) and human clinicalstudies (58).
In tumour animal models, the comparative antitumour effectof Aureobasidium pullulans‑derived β‑glucan has been shown
to be significantly higher than those of other glucan types (61).
The administration of the AFO‑202 β‑glucan, lead to an increasein the anti‑tumour immune response and its maintenance atnormal levels, similar to the levels of control groups without
chemotherapy administration (62). The percentage of tumour
size decrease has been reported to be higher when A. pullulans
β‑glucan was administered (63) along with chemotherapy thanwith chemotherapy (64) alone. In another study, 11 healthy
human volunteers consumed 15 g AFO‑202 β‑glucan orally
three times per day for 1 month. NK cell cytotoxic activity
was assessed using peripheral blood provided by the volunteers
before and after the intake. NK cell activity was evaluated using
the 51Cr release test with an effector to target (E/T) ratio of 50/1,
using peripheral blood mononuclear cells as functional cells andK562 cells as target cells. The rate of increase of the cytotoxic
activity was 90.9% (62).
Fungal β ‑glucans have been shown to increase NK cell
activity in cancer patients of different age groups (65) andthis further attests to the significance of its application in aged
individuals and in those who are immunocompromised due
to cancer.

The evolution of the immune system includes a curve
upwards during cancer, with contributions from viruses andchronic inflammation. With lifestyle and metabolic disorders
having become major healthcare‑related issues in the latter
half of the past century, and with microinflammation serving
as the underlying mechanism leading to cancer in such indi‑viduals, senile immune system weakness or inflammaging are
unavoidable. These changes may occur in any individual, eventhough they may not present with chronic inflammation. All theaforementioned factors adversely affect the immune system.
Addressing this issue requires a holistic approach that canpotentially act against viral and other infections, inflammationand metabolic disorders, in addition to acting as a continuous
supportive mechanism for the prevention of the immune surveil‑
lance system weakening. Apart from these factors, genetic
components of the immune system or genetically prone cancer
types may further lead to immune system weakness. Genetics
should be also considered, as in these individuals vulnerable tocancer, the time at which immune system weakness develops
or the deterioration of the cancer aggressiveness may occur
remains unknown. A continuous vaccine adjuvant approach
could include the use of food supplements, including β‑glucan.
Although it remains unknown whether immunoenhancement
will completely achieve treating any cancer already formed, it
is suggested as a potential strategy to address the periodic orintermittent jeopardy to the immune system. The duration of
immune system weakness after surgery, as well as the immune
system weakness induced by chemo‑ or radiotherapy, requires
definite examination; immunosuppression is considered amajor reason for treatment failure in cancer (66). Treatment
strategies to overcome immune system weakness after cancer
therapies require large‑scale translational and clinical research.
It is hoped that this kind of research will yield further insights
into how chemotherapy, surgery or radiotherapy‑related cancer
treatments can be supplemented by B‑VACCIEN (Fig. 1), toalleviate side‑effects. This goal can be achieved by effectively
engaging the immune system, in order to reduce cancer‑adverse
reaction‑related morbidity and mortality.
β‑glucans are effective chemotherapy adjuvants, due to theirprotective antioxidant effects against chemotherapy‑induced
cytotoxicity (67). It is significant to underline that a random‑ized phase I/II trial studying the side effects and optimal doseof OPT‑821 (a saponin‑based immunoadjuvant OBI‑821) withvaccine therapy when given together with β‑glucan, as wellas the examination of the effectiveness of this regimen in thetreatment of younger patients with neuroblastoma is currently
ongoing (68).
While several animal studies have demonstrated promising
results for the use of a β‑glucan vaccine adjuvant approachfor the treatment of cancer, human studies fall short of the
expected outcome (69). This may be attributed to the sourceof the β‑glucan; careful selection of the source and the process
involved in the extraction‑purification is essential for an effi‑
cient antitumour response. A comparative study on the various
types of β‑glucans in different tumours and stages will be alsoessential for the development of additional, more effective
β ‑glucan vaccine adjuvant therapeutics. Moreover, tumour
microenvironment is extremely complex and is a challenge forthe successful combination of β‑glucan and various cancer ther‑
apies, including immune‑modulating Abs. The overexpression

ONCOLOGY REPORTS 47: 14, 2022

7

Figure 1. Illustration summarizing the β‑glucan vaccine adjuvant approach to treating cancer via immune enhancement (B‑VACCIEN). ROS, reactive oxygen
species; PAMP, pathogen‑associated molecular pattern. *https://doi.org/10.1080/21645515.2021.1880210; **safety data of the AFO‑202 strain of black yeast
Aureobasidium pullulans produce: Nichi Glucan.

of some membrane complement regulatory proteins can limit
the β‑glucan‑primed immune cell infiltration into tumours.
Additional strategies of modifying the tumour microenviron‑ment are required to overcome these challenges (35).
6. Conclusion
Several factors and pathogenic processes have been identified,that can predispose an individual to a high risk of developing
cancer and/or enable the progression of cancer, including:i) Chronic and microinflammation caused by infections,
aging or metabolic disorders, including diabetes; ii) genetic
causes; and iii) immune system weakness, either due tocancer or cancer therapy. Therefore, the prevention of cancer
in the general population and in patients undergoing surgicalor chemotherapeutic treatments is practically feasible, only
if a consistent and simple approach can be followed, as forexample a nutritional supplement to combat the compromiseof the immune system and chronic microinflammation. The
current review presented evidence of a BRMG, with regards to
its potential function as a β‑glucan vaccine adjuvant approachfor the treatment of cancer through immunoenhancement.
This approach may aid in the treatment of cancer in specificimmunocompromised populations, as it induces a wide
variety of biological response modifications. For example,
the BRMG application may balance metabolic parameters,
including blood glucose and lipid levels, increase peripheral

blood cell cytotoxicity against cancer and alleviate chemo‑
therapy‑induced side effects in animal models. Thus, the useof a β‑glucan vaccine adjuvant approach was suggested for thetreatment of cancer via immunoenhancement as a potential
strategy for a long‑term prophylaxis in immunocompromised
individuals or genetically prone to cancer.
Acknowledgements
The authors would like to thank Mr. Yasunori Ikeue, Mr. Mitsuru
Nagataki and Mr. Takashi Onaka, (Sophy Inc.), for providing
the necessary technical clarifications, as well as Loyola‑ICAM
College of Engineering and Technology (LICET) for providing
the necessary infrastructure for the present study.
Funding
No funding was received.
Availability of data and materials
Not applicable.
Authors' contributions
NI, VDD, KR and SJKA contributed to the conception anddesign of the study. RS performed the literature search and8

IKEWAKI et al: B-VACCIEN ADJUVANT TO COMBAT CANCER IN SPECIFIC IMMUNOCOMPROMISED INDIVIDUALS

data analysis. SJKA and SP confirm the authenticity of all theraw data. SJKA and SP drafted the manuscript. KSR, SV, HO,
TK, GK, SS, SRBK and MI performed the critical revision of
the manuscript. All authors contributed to manuscript revision,
read, and approved the submitted version.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
SJKA is a shareholder in GN Corporation, Japan which in turnis a shareholder in the manufacturing company of the AFO
202 β‑glucan.
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