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Journal of Nutritional Biochemistry 85 (2020) 108428

REVIEWS: CURRENT TOPICS

The immunoregulatory function of polyphenols: implications in cancer immunity

José Tarcísio Giffoni de Carvalho, Debora Da Silva Baldivia, David Tsuyoshi Hiramatsu de Castro,
Helder Freitas dos Santos, Cintia Miranda dos Santos, Alex Santos Oliveira, Tamaeh Monteiro Alfredo,
Kellen Natalice Vilharva, Kely de Picoli Souza, Edson Lucas dos Santos⁎
Research Group on Biotechnology and Bioprospecting Applied to Metabolism, Federal University of Grande Dourados, Dourados, Brazil

Received 20 November 2019; received in revised form 14 May 2020; accepted 18 May 2020

Abstract

Polyphenols have demonstrated several potential biological activities, notably antitumoral activity dependent on immune function. In the present review, we
describe studies that investigated antitumor immune responses influenced by polyphenols and the mechanisms by which polyphenols improve the immune
response. We also discuss the limitations in related areas, especially unexplored areas of research, and next steps required to develop a therapeutic approach
utilizing polyphenols in oncology.
© 2020 Published by Elsevier Inc.

Keywords: Polyphenols; Antitumor immune response; Cancer therapy; Natural compounds; Immuneregulatory properties

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Immune response against tumor cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.1. Role of NK cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.2. T cell response against tumor cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.3. Innate cell signaling to activate T cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.4. Therapeutic or prophylactic vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.4.1. Immunogenic cell death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.4.2. Tumor-based vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.5. Immune checkpoints and Treg cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.6. Tumor immune escape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3. Immune regulation by polyphenols in the cancer microenvironment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.1. Polyphenols promote NK cell activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.2. Polyphenols as therapeutic or prophylactic vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.3. Polyphenol activation of Th1/CD8+ T cell-mediated immunity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.4. Polyphenols suppress Treg activation and function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.5. PD/PD-L1 checkpoint modulation by polyphenols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.6. Polyphenols suppress TAMs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4. Bioavailability of polyphenols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

⁎ Corresponding author.
E-mail address: edsonsantosphd@gmail.com (E.L. dos Santos).

https://doi.org/10.1016/j.jnutbio.2020.108428
0955-2863/© 2020 Published by Elsevier Inc.
2 J.T.G. de Carvalho et al. / Journal of Nutritional Biochemistry 85 (2020) 108428
1. Introduction
Polyphenols are compounds synthesized by plants for protection
against radiation, mechanical damage and microbial infection [1].
Polyphenols have structural variability and are commonly classified as
flavonoids, phenolic acids, tannins and stilbenes. The main differences
among polyphenols are in the number of phenol rings together with
one or more hydroxyl radicals [2,3].
Several potential biological activities have been described for
polyphenols, such as antitumor activity [4,5], and these molecules
have great potential for immune regulation [6,7]. In recent years, there
has been an increasing emphasis on the importance of the immune
response against cancer and the search for therapies that can interact
with the immune system to eliminate tumor cells [8–10]. In this context,
phenolic compounds may emerge as adjuvant therapies, as indicated by
the studies that are already available, and new therapeutic alternatives.
Realizing these potentials still depends on the acquisition of more data,
and many questions remain to be answered.
In this review, we describe and discuss recent studies that show
that polyphenols have antitumor activity dependent on adaptive
immunity and focus on the mechanism through which they act, as well
as the next steps for the progression of this field to develop future
therapeutic approaches.
2. Immune response against tumor cells
CD8+ T cells are the major weapons used by the immune system to
eliminate tumor cells, but other cell types also perform important roles
in the antitumor immune response, including natural killer (NK) cells
and macrophages [11–14] (See Fig. 1).
An adequate CD8+ T cell response against tumor cells depends on T
cell activation and involves some key points: first, phagocytosis by
antigen-presenting cells (APCs) and the presentation of tumor antigens
via major histocompatibility complex class I (MHC-I); second, CD8+ T
cell differentiation into cytotoxic T lymphocytes (CTLs); and third,
recognition of MHC-I on target cells by CTLs, resulting in the elimination
of tumor cells through the caspase cascade [15,16].
There has been great progress in understanding the regulation of
these stages, particularly in regard to the concepts of immunogenic death
and immune checkpoints, which has allowed the elucidation of new
antitumor mechanisms that can be targeted by new therapeutic agents.
2.1. Role of NK cells
NK cells are one of the main effectors against cancer and function
via direct cytotoxicity and/or cytokine and granule secretion to
eliminate cancer cells, like CD8+ T cells (see below) [17–19]. NK
cells are characterized phenotypically by absence in expression of the
cluster of differentiation (CD)3 of T cells and by expression of CD56 in
humans (CD3 −CD56 +), and expression of NK1.1 + in mice or
expression of NKp46+ in both species [20]. Human NK cells can be
further divided into two distinct subsets on the basis of their level of
CD56 expression and the presence or absence of CD16; human NK cells
can be identified as positive to CD16 marker and by lower expression
of CD56 cells (CD16+CD56low), which are the most numerous NK cells
in the blood, or as negative for CD16 with higher expression of CD56
(CD16−CD56high cells), which are characterized as a less mature
population [21].
NK cells detect and eliminate tumor cells that are deficient MHC-I
molecules (missing self), exhibit up-regulated expression of stress
ligands recognized by activating NK cell receptors (induced self) or are
coated with antibodies specific for tumor antigens, which enable
recognition by NK cells expressing the fragment crystallizable (Fc)
receptor and trigger antibody-dependent cell-mediated cytotoxicity
[17,18,22].
NK cells express receptors from three major families: (a) killer cell
immunoglobulin (Ig)-like receptors (KIRs), (b) natural cytotoxicity
receptors (NCRs) [23] and (c) Lectin-like Receptors. NK cell activation
depends on the balance between positive and negative signals from
members of these families. For example, NKG2D (a positive-signaling
member of the Lectin-like Receptor family) is activated by sequences A
and B (MICA and MICB), which are not present on the cell surface in
most healthy tissues but can be expressed on transformed cells and
tumor cells [24,25].
2.2. T cell response against tumor cells
CD8+ cytotoxic T cells are primarily responsible for the recognition
of cancer through molecules expressed on the surface of tumor cells,
including MHC class I [26], and initiate apoptotic processes mediated
by members of the tumor necrosis factor (TNF) cytokine family [27,28]
and the release of granules.
Perforin forms a pore in the membrane of a target cell that allows
molecules to enter malignant cells. Granzymes are serine proteases
that cleave the proteins inside a cell, inducing apoptosis by caspase-
independent (Granzyme B) [29,30] or caspase-dependent pathways
(Granzyme A) [27,31]. The binding of a ligand in the TNF family to the
corresponding death receptor is an important trigger for apoptosis
[32–35]. Active T cells can secrete TNF or tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL) or overexpress CD95 ligand
(CD95L) on their cell surface, and these molecules bind to “death
receptors” on target cells to initiate apoptosis by interacting with the
corresponding receptors, TNFR, Fas and the death receptors DR3, DR4
and DR5, respectively [27,28].
CD4+ T cells play an important role in the tumor cell elimination
mediated by CD8+ cytotoxic T cells by supporting the activation and
expansion of CD8+ T cells and the generation and maintenance of
CD8+ T cell memory. Following activation, CD4+ T cells are further
differentiated into T helper 1 (Th1) cells that act by producing
cytokines, such as interferon-gamma (IFN-γ) and interleukin (IL)-2, to
promote the CD8+ T cell response [26,36]. In addition, CD4+ T cell help
is also dependent on CD40-CD40 L cell–cell interactions. CD40
signaling triggers the up-regulation of the expression of costimulatory
molecules, such as CD86 and OX40 ligand, in APCs, which provides a
signal via the corresponding receptors on CD8+ T cells, resulting in
strong activation and effector function [37]. Finally, Th1 cytokines play
important roles in macrophage activation and tumor elimination [38].
Accordingly, both the number and function of tumor-specific CTLs
are significantly enhanced in the presence of tumor-specific CD4+ T
cell responses, whereas depletion of CD4+ T cells facilitates tumor
progression and reduces the survival of tumor-bearing hosts,
indicating the importance of tumor-specific CD4+ T cell help in
maintaining tumor-reactive CTL functions in vivo [39]. In addition, the
efficacy of antitumor responses induced by the combined adminis-
tration of human CD4+ and CD8+ T cells is notably better than that
induced by applying CD4+ or CD8+ T cells alone [40,41].
CD4+ T helper cells are the central cells in antitumor immunity that
further differentiate into Th1 cells, which act by producing cytokines,
mainly IFN-γ and IL-2, to promote CD8+ T cell immunity and
macrophage activation. When properly activated by IFN-γ, macro-
phages are able to directly eliminate cancer cells [41]. They can also
support the adaptive immune response through the presentation of
tumor antigens and the production of chemokines and cytokines to
recruit and activate cytotoxic CD8+ T cells and NK cells [42].
2.3. Innate cell signaling to activate T cells
To engage adaptive immunity in a manner that results in diversity,
specificity and memory, antigens must be processed and presented to
T cells [43]. Presentation is mediated by MHC class I and II molecules
 J.T.G. de Carvalho et al. / Journal of Nutritional Biochemistry 85 (2020) 108428
[44]. MHC class I and II molecules are similar in function: they display
short peptides to the cell surface, allowing these peptides to be
recognized by CD8+ and CD4+ T cells, respectively, and subsequently
initiate T cell activation. Both MHC I and II molecules participate in T
cell activation, but MHC-I also participates in the recognition of target
cells (tumor) by CD8+ T cells during cytotoxic elimination [45].
Dendritic cells (DCs) are the most effective APCs in the innate
immune system [46,47]. These cells act as sentinels with the greatest
ability to capture and deliver antigens with adequate signals to induce
T cell activation and the T cell response [47].
During activation and differentiation into effector T cells (T eff),
naïve lymphocytes receive two signals when they interact with antigen-
presenting cells [48,49]. The first signal is the antigen signal provided
through the MHC molecule to the T cell receptor. For the second signal, a
costimulatory signal is delivered when members of the B7 family (CD80
or CD86) interact with the receptor CD28 on T cells.
2.4. Therapeutic or prophylactic vaccination
In the context of emerging therapies for cancer, two different
vaccination approaches, specifically therapeutic and prophylactic
vaccines, have shown great potential. Preventive vaccines induce
pathogen-specific T cells to establish immune memory, preventing
tumor recurrence, while therapeutic vaccines raise a specific immune
response against an established tumor. Despite working by different
mechanisms, immunogenic cell death and tumor-based vaccines both
target DCs for modulation, resulting in T cell activation and memory.
2.4.1. Immunogenic cell death
Recent advances describe that cell death, under certain circum-
stances, can subsequently result in T cell activation and the
development of adaptative immunity, which is defined as immuno-
genic cell death (ICD) [50,51]. The signals that mediate the
immunogenicity of tumor cells involve endogenous molecules
released from dying cells, which are danger-associated molecular
Imunogenic
Cell
Death
DAMPs
A
B T CD8+
Tumor Eliminaon
M1 cells NK
D
C
E MHC-
IFN-γ
T CD8/CD4+ cells
Fig. 1. Cancer immunity: (A) NK cells represent the first line of defense against a tumor cell. (B) Immunogenic cell death results in DAMP release, which increases the expression of
costimulatory molecules (CD80/86) by APCs. (C) Tumor peptide presentation to T cells leads to subsequent activation. (D) CD8+ T cell-mediated elimination of tumor cells occurs via
MHC-I recognition. (E) Cytokines from T helper cells enhance macrophage activity.
3
patterns (DAMPs), such as heat shock proteins (HSP) 70 and 90,
calreticulin (CRT), high-mobility group box 1 (HMGB1) and adenosine
triphosphate (ATP) [52,53]. These DAMPs are recognized by toll-like
receptors expressed by APCs, resulting in MHC presentation together
with B7 membrane expression for costimulation [54].
Importantly, interest in the induction of ICD has been increasing as
a potential emergent therapy since ICD, like vaccines, has the ability to
induce immunological memory and, in subsequent carcinogenic
processes, to raise a fast and strong immune response [55,56].
2.4.2. Tumor-based vaccines
In the context of emerging therapies for cancer, tumor-based
vaccines have shown great potential. Basically, a tumor-based vaccine
relies on delivering tumor antigens directly to APCs, after which, when
the APCs home to secondary lymphoid organs, DC activity leads to an
enhanced tumor-specific T cell-mediated immune response and
enhanced antitumor effects [57,58]. To achieve this purpose, different
types of cancer vaccines have been developed, i.e., cell-based vaccines
that involve autologous DC activation ex vivo and injection into
patients [59], protein/peptide derivates for intratumoral administra-
tion [60] and gene-based vaccines, including RNA and DNA vaccines
that transfect normal tissue to express tumor antigens [58].
2.5. Immune checkpoints and Treg cells
The immune system uses many checkpoints to ensure that CD8+ T
cells react specifically to tumor cells without causing injury to healthy
cells [61,62]. Two well-described checkpoint molecules, cytotoxic T
lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1),
act as negative regulators of T cell function and have been associated
with immune evasion in cancer [63]. CTLA-4 is a CD28 homolog that
has much higher binding affinity for B7 than does CD28 [64]; however,
unlike that of CD28, the binding of CTLA-4 to B7 does not produce a
stimulatory signal. As such, this competitive binding can prevent the
transduction of the costimulatory signal normally provided by CD28:B7
T CELLS ACTIVATION
1° Signal
MHC TCR
T CELLS
APC
APC 2° Signal
CD80/86 CD28
T CD4+
T CD8 x TARGET CELLS
CELL DEATH SIGNAL
CD28
I TCR
TUMOR
T CD8
EFFECTOR SIGNAL
CELLS
FAS FAS-L
Granules
4 J.T.G. de Carvalho et al. / Journal of Nutritional Biochemistry 85 (2020) 108428
binding [48]. Furthermore, the engagement of PD-1 with its coreceptor,
programmed death-ligand 1 (PD-L1), which is expressed by cells in the
absence of stress, results in the down-regulation of T cell activity,
including antitumor activities, thereby restricting cell killing [65].
To prevent overactive inflammatory responses, the immune
system generates regulatory T (Treg) cells [66,67]. The differentiation
of this subset is driven by the transcription factor Foxp3 [68], and these
cells exert suppressive effects via high expression of CTLA-4 [48] and
secretion of key anti-inflammatory cytokines, notably transforming
growth factor-β (TGFβ) and IL-10 [68].
2.6. Tumor immune escape
Historically, the first mechanism described for evasion of the
immune system, especially CD8 + T cells, was a lack of MHC-I
expression, and more recently, the immunoediting of tumor cells by
NK cells has been shown to lead to tumor variants that can evade NK
cell-mediated responses [25,69]. These mechanisms include the
secretion of immunosuppressive factors, shedding of ligands for
activating NK cell receptors and induction of ligands for activating
NK cell receptors on healthy cells that can serve as decoys [25,69].
Finally, evidence has shown resistance to apoptosis mediated by
overexpression of decoy receptors (DcRs; DcR1, DcR2 and DcR3),
which is useful for tumors since these molecules compete with death
receptors for death ligand binding, thus inhibiting apoptosis [25,69]
(See Fig. 2).
In recent years, other mechanisms have been proposed, especially
mechanisms by which tumor cells evade the CD8+ T cell response,
suggesting two main strategies. The first strategy is decreased
checkpoint activation or recognition by T cells [70]. For example,
triple-negative breast cancer, the most aggressive type of all breast
tumors, is characterized by a lack of expression of hormone receptors
and human epidermal growth factor receptor 2 (HER2), was reported
by an increase in the expression of PD-L1 [71,72]. Over the past few
years, a great advance in cancer treatment has been the development
of monoclonal antibodies that serve as immune checkpoint inhibitors,
Tumor Progression, angiogenesis,
and resistance
VEGF
IL10, IL4
B CD80/86
C CTLA4
A
↓MHC-I
NK E
↑PD-L1
M2 cells M1 cells
T CD8/CD4+ cells
Fig. 2. The red line indicates the mechanism of tumor escape. (A) Tumor-secreted factors induce alternative activation in macrophages, leading to the secretion of soluble factors
important for tumor growth and metastasis. (B) Tumor cells evade NK cell vigilance by shedding ligands for activating NK cell receptors and inducing the expression of ligands for
activating NK cell receptors on healthy cells. (C) Factors secreted by tumor cells increase CTLA4 expression. (D) This balance influences the activation of Tregs, which inhibit effector T
cells. (E) Targeted tumor cells escape CD8+ T cells by increasing PDL1 expression.
such as anti-PD1 (pembrolizumab and nivolumab), anti-PD-L1
(MPDL3280A) and anti-CTLA4 (ipilimumab) antibodies, to overcome
the ability of cancer cells to resist immune responses and to stimulate
T cell activation. These inhibitors have shown remarkable success in
enhancing the effector antitumor response in different malignancies,
especially in melanoma [65] and lung cancer [73], but the cost of
treatment per patient is very expensive.
For the second approach, cancer cell secretion of suppressive
molecules such as IL-10, TGF-β and vascular endothelial growth factor
(VEGF) skews the T cell population toward an inadequate profile of T
cell subsets, such as increased Treg or T helper (Th) 2 activation
instead Th1 activation, or induce alternatively activated macrophage
polarization [74,75].
Substantial clinical and experimental evidence indicates that there is
an abundance of macrophages in most tumor types [76,77]. Macro-
phages may be activated in a way dependent on the microenvironment
as “classically activated M1” macrophages via the proinflammatory
molecule IFN-γ or lipopolysaccharide or “alternatively activated M2”
macrophages induced by IL-4 or IL-13 [38,78]. While M1 macrophages
exhibit antitumor activity, M2 macrophages can be used by tumors to
promote tumor progression and escape and are commonly referred to
as tumor-associated macrophages (TAMs) [79]. TAM-induced immune
suppression is mediated by the expression of T cell immune checkpoint
ligands, such as PDL1, and the secretion of several cytokines, such as IL-
10 and TGFβ, and important growth factors essential in metastasis,
especially VEGF [76].
3. Immune regulation by polyphenols in the cancer microenvironment
Recent findings indicate that polyphenol antitumor effects are at
least partially dependent on the immune response, especially on T
cell modulation [80–82]. The mechanism by which polyphenols
improve the immune response has been investigated in a few
publications. The immunoregulatory effects of polyphenols are
summarized in Fig. 3 and Table 1. Although the topics presented
Tumor escape
mechanism
CELL DEATH SIGNAL
MHC-I TCR
T CD8
APC STOP SIGNAL
CELLS
CD28
APC
CELL DEATH SIGNAL
TCR
TUMOR
T CD8
STOP CD8 CELLS
D
PD-L1 PD1
↑T reg cells
 J.T.G. de Carvalho et al. / Journal of Nutritional Biochemistry 85 (2020) 108428 5

Table 1
Immunoregulatory and antitumor effects of polyphenols
Immune effect/mechanism Polyphenol/concentration Model Outcome Ref.

Activation of NK cells
Resveratrol (25 μM, 24 h) Promyeloblastic leukemia ↑ NK cell-mediated leukemia cell lysis [83]
↑ NKG2D
Resveratrol (37 μM, 48 h) Molt4, THP1, KG1 and Jurkat cells ↑ NK cell-mediated leukemia cell lysis [84]
↑ NKG2D
↑ ULBP1, ULBP2, ULBP3 and MICA/B
Resveratrol (1 g/day/4 weeks) Leukemic patients ↑ NKG2D+ cells [85]
↑ CD56+ NKG2D+
Polyphenol fraction of C. spinosa (75 mg/kg/s.c/3 Melanoma in vivo NK cells and CD69+ cells activated [86]
days)
Extract from persimmon leaves; 2 g/kg/o.g./10 Liver tumor in vivo ↑ Promoted NK cell cytotoxicity [87]
days) ↑ IL-18

Polyphenols acting as a
therapeutic or preventive
vaccine
Polyphenol fraction of C. spinosa (75 mg/kg/s.c/3 Melanoma cell and mouse models ↑ CRT, ATP and HMGB1 [88]
days) ↑ Central memory (CD62L+CD44+) CD8+ T cells
Polyphenol fraction of C. spinosa (75 mg/kg/s.c/3 Breast cell and melanoma mouse ↑ Calreticulin, HMGB-1, and ATP [89]
days) models ↑ Cytokines
Resveratrol 0 (25 and 50 μM, 48 h) Ovarian carcinoma mouse model ↑ Calreticulin, HMGB-1, and ATP [90]
Pretreatment produced a vaccine-like effect that
significantly inhibited the growth of a subsequent
inoculated xenograft tumor
EGCC (0.5 mg/mL/o.g./ 5 days) Murine skin tumor model Improved DNA vaccination with LAMP [101]
↑ T cell-mediated immune response and antitumor
effects
Curcumin in micelles (40 mg/kg/i.v./5 days) Melanoma in mice ↑ IL-6 and CCL-2 [102]
↓ TNF-α and IFN-γ levels

Polyphenols induction of
Th1/CD8+ T cells
Resveratrol (1, 2.5 and 5 mg/kg/i.i./6 days) Renal carcinoma in vivo ↑ Th1 cytokines with predominance of IFN-γ [100]
↓ Th 2 cytokines, such as IL-4 and IL-10
Activated CD69+ CD8+ T cells
↑ Perforin, granzyme B and FasL
Rutin (6 or 12 mg/kg/o.g./6 weeks) Murine myelomonocytic leukemia cell ↑ T cells (CD3+) and B cells (CD19+) [103]
line (WEHI-3) in BALB/c mice ↑ Macrophage phagocytosis
Caffeic acid 40 or 80 mg/kg Ehrlich ascites tumor ↑ Th1 cytokines: IL-2, IL-12 and IFN-γ [119]
↓ Th 2 cytokines: IL-4 and IL-10
Linalool (227 μM, 48 h) and p-coumaric acid (478 PBMCs+ A549, T-264 47D, SW-620 or ↑ IFN-γ, IL-12p40, IL-1β and TNF-α [104]
μM, 48 h) Hep G2 cells ↑ CD40/CD40L
Resveratrol low (10 and 25 μM, 24 h) high (60 μM, PBMCs+ HT29 or RKO cells Dose-dependent response [33]
24 h) ↑ IL-1β and IL6 at low dose
↓ IL-1β, IL6, IFN-γ and TNF-α at high dose

Polyphenols suppress Treg

function and activation
Curcumin, 3 g/day/2 weeks)
Curcumin, 3 g/day/4 weeks
EGCG-rich extract green tea (4602 mg green tea/ Chronic lymphocytic leukemia (CLL) ↓ Reductions in circulating lymphocytes and Treg [107]
189 mg of EGCG/6 days)
Polyphenol fraction of C. spinosa, 75 mg/kg
Lung cancer patients (n=30) ↓ CD4+CD25+Foxp3+ Treg cells [105]
↑ IFN-γ-producing Th1 cells
Colon carcinoma patients (n=40) ↓ CD4+CD25+Foxp3+ Treg cells [106]
↑ IFN-γ-producing Th1 cells
patients (n=20) cells
↓ IL-10 and TGF-β
↑ Activity of CD8+ T cells
Melanoma in BALB/c or C57BL/6 mice ↓ IL-10 levels and FoxP3 expression [86]

Polyphenols modulate
immune
checkpoints
Apigenin (30 μM, 4 h) and curcumin (25 μM, 4 h) Melanoma cells ↑ PD-L1 expression [110]
Resveratrol (50 μM, 24 h) and piceatannol (50 μM, Breast cells ↑ PD-L1 expression [112]
24 h)
Bisdemethoxycurcumin (3 mg/kg/i.v/3 weeks) Bladder cancer mouse model ↓ PD-1 expression [111]
↑ Activity of CD8+ T cells
↑ IFN-γ and granzyme B
Resveratrol (100 mg/kg/s.c) Ovarian carcinoma mouse model ↓ Tumor growth [90]
↑ Xenograft progression after depletion of CD8+ T
cells

Suppression of TAMs
EGCG (10 mg/kg /i.p./3 days) Balb/c tumors induced by the murine ↓ Chemokines: CSF-1 and CCL-2 [115]
breast cancer cell line 4 T1 ↓ Infiltration of macrophages
↑ miR-16

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Table 1 (continued)
Immune effect/mechanism Polyphenol/concentration Model
Curcumin (1.28 mM) + epicatechin (320 μM) Mice with tumors induced by GL261 ↓ Tumor growth
gallate + resveratrol (4 mM/ i.p./5 days) mouse glioblastoma cells
Curcumin (1.28 mM) + epicatechin (320 μM) Mice with tumors induced by TC-1 ↓ Tumor growth
gallate + resveratrol (4 mM/i.p./5 days) cells infected with HPV
Resveratrol (25 μM, 24 h) Lung cancer cells
Resveratrol (5–50 μM, 24 and 48 h) Lymphatic vessels
Rutin (200 μM/kg/bw/5 day) B16F-10 melanoma cells in C57BL/6 ↓ VEGF and IL-1β
mice
i.p.: intraperitoneal; i.v. intravenously; s.c. subcutaneous injection; o.g. oral gavage.
here are all connected, for ease of understanding, our discussion is
divided into six topics:
I. Polyphenols promote NK cell activation
II. Polyphenols as therapeutic or prophylactic vaccines
III. Immune checkpoint modulation by polyphenols
IV. Polyphenol-mediated activation of Th1/CD8+ T cell immunity
V. Polyphenols suppress Treg activation and function
VI. Polyphenols suppress TAMs
3.1. Polyphenols promote NK cell activation
Previous studies have shown that resveratrol sensitizes leukemia
cell lines to NK cell-mediated antitumor effects in cocultures of
CD3+CD56+ cells isolated from the peripheral blood mononuclear
cells (PBMCs) of healthy volunteers. Hu et al. [83] found inhibition of
the growth of promyeloblastic leukemia KG-1a cells in the presence of
resveratrol. This effect was correlated with an increase in the cell-
surface expression of NKG2D ligands and DR4, coupled with a down-
regulation of the cell-surface expression of DcR1 on the KG-1a cells. In
addition, these effects were ameliorated by blocking NKG2D ligands or
TRAIL. Espinoza et al. [84] showed that pretreatment of leukemia cells
with resveratrol promoted an increase in the sensitivity of leukemic
cell lines (Molt4, THP1, KG1, and Jurkat) to killing by NK cells and
induced variable increases in the expression of NKG2D in NK cells and
that of NKG2D ligands, including MICA, ULBP1, ULBP2 and ULBP3. In
fact, leukemia cell lysis was abrogated by blocking NKG2D. Impor-
tantly, these studies showed that resveratrol could induce an
enhancement in NK activities at low concentrations (25-37 μM) but
a suppressive effect at high concentrations (60 μM).
An in vivo examination of the effects of administered daily
resveratrol (1000 mg) for 4 weeks to nine healthy subjects showed
an increase in NKG2D+ T cell and CD3−CD56+ NKG2D+ NK cell
numbers, while CD8 + and CD4+ T cell and CD19 + B cell numbers did
not change [85]. The limitations of the study design and the lack of
appropriate number of patients suggest further evaluation to
confirm the positive effect of resveratrol in cancer patients by NK
actions. As mentioned before, in vitro studies showed that resveratrol
could promote a dual effect on NK activities at different concentra-
tion. Thus, a study with a range of dose administrated could help to
understand the in vivo effect of resveratrol in NK activities in cancer
patients.
Together, these findings show that resveratrol increases NK cell
activities in vitro and in vivo, is safe in humans and acts through the
modulation of the NKG2D receptor/NKG2D-L system and activation of
the TRAIL pathway. In spite of the increase in NKG2D+ T cell numbers
observed after the administration of resveratrol to healthy subjects,
this suggests the need for a future clinical study evaluating the
relationship between resveratrol intake and the prevention of cancer.
Outcome Ref.
[116]
↓ M2: ARG1high iNOS low IL-12 low IL-10 high
↑ M1: ARG1 low iNOS high IL-12 high IL-10 low
[117]
↓ M2: ARG1 high iNOS low IL-12 low IL-10 high
↑ M1: ARG1 low iNOS high IL-12 high IL-10 low
↓ M2 polarization induced by lung cancer cells [113]
↓ Lymphangiogenesis ↓ IL10 and VEGF in M2 [114]
macrophages.
[118]
↑ TNF-α
Furthermore, Lasso et al. [86] observed increased numbers of total
NK and CD69+ activated NK cells after C. spinosa (P2Et), a plant native
to South America, treatment in B16F10 mouse melanoma cells but did
not investigate the associated mechanisms. Chen et al. [87] evaluated
the potential to induce NK activity with an extract rich in flavonoids
from persimmon (traditional medicine in Asia) in liver tumor-bearing
mice. This extract promoted NK cell cytotoxicity and enhanced IL-18
production, possibly by stimulating macrophages, thereby up-
regulating the NK cell-mediated antitumor immune response. These
extracts are rich in polyphenols, particularly flavonoids.
NK cells represent the first line of defense against a tumor process,
therefore, emerging therapies that modulate their activity may
represent a new therapy. In this context, polyphenols appear as a
new strategy approach in cancer treatment, but further research is
needed to more properly address this topic, such as to confirm effect of
resveratrol, and evaluate other polyphenols such as quercetin, rutin
and curcumin on the NK function and activity.
3.2. Polyphenols as therapeutic or prophylactic vaccines
One group evaluated the potential of P2Et to induce immunogenic
cell death in two different publications. Gomez-Cadena et al. [88]
found that P2Et induced apoptosis in B16F10 mouse melanoma cells.
Confirming immunogenicity, the protective effects of P2Et treatment
were abolished in immunodeficient mice. Moreover, P2Et induced the
expression of DAMPs, such as ATP, CRT and HMGB1. Finally, P2Et-
treated cells were injected into C57BL/6 mice, showing that these
cells worked as a cell vaccine to delay further tumor growth.
Central memory (CD62L+CD44+) CD8 + T cell levels were also
found to be increased. Urueña et al. [89] found a similar effect
when evaluating the effect of P2Et on breast tumor 4T1 cells.
Positive results were found for ICD markers, such as calreticulin
expression, HMGB1 and ATP secretion. Primary tumor control was
improved by vaccination with P2Et-pretreated 4T1 cells, yielding
long-lasting ex vivo multifunctional CD4 + and CD8 + T lymphocytes
that secreted IL-2, TNF-α, IL-4, IL-5 and IFN-γ after specific 4T1 cell
stimulation.
In another study, Zhang et al. [90] observed that resveratrol
induced apoptosis in ovarian carcinoma cells by stimulating cell-
surface exposure of CRT, secretion of HMGB1 and release of ATP.
Moreover, the pretreatment with resveratrol worked a vaccine since it
significantly inhibited the growth of subsequently inoculated xeno-
graft tumors. The authors further characterized increases in both
mature dendritic cell and cytotoxic T cell numbers in xenograft tumors
in response to resveratrol treatment, which also inhibited TGF-β
production and stimulated both IL-12p7 and IFN-γ secretion.
Although several studies have demonstrated the cytotoxic activity
of polyphenols in a large number of cancer lines, it is not clear when
polyphenols induce DAMP release and immunogenic cell death. In
fact, in vitro curcumin treatment induces apoptosis in renal cancer
 J.T.G. de Carvalho et al. / Journal of Nutritional Biochemistry 85 (2020) 108428 7

Improve
Imunotherapy
Tumor vaccine Immune response
NK adjuvant Checkpoints:
PD-L1
T CD8+

M2 cells Cytotoxic
T CD8+
activity
POLYPHENOLS APC

T CD4+
M1 cells T reg

Imunogenic
Cell DAMPs
Death release Th2

Th1

Fig. 3. The antitumor and immunoregulatory actions of polyphenols: polyphenols as resveratrol and gallotannin-rich fraction obtained from Caesalpinia spinosa (P2Et) act to enhance NK
cell antitumor activity. Curcumin, epicatechin gallate (EGCC), resveratrol and rutin inhibit the protumoral M2 polarized macrophages and enhancement the polarization of
macrophages toward the M1 phenotype, which exerts antitumor effects. EGCC and curcumin improved the response from tumor-based vaccines to induce an in vivo adaptive immune
response against a tumoral antigen. Resveratrol and P2Et induce immunogenic cell death and DAMPs release, which, in turn, induce cellular immunity by activating Th1 cell responses. In
addition, an epigallocatechin-3-gallate (EGCG)-rich extract green tea, curcumin, and P2Et improve cancer immunity by shift from a Th2 or Treg balance to a Th1 response against the
tumoral antigen. Bisdemethoxycurcumin suppresses PD-L1 expression, thus enhancing the TCD8+ cytotoxically activity and immune surveillance. On the contrary, other polyphenols
such as curcumin, apigenin, resveratrol and piceatannol increase PD-L1 expression and might improve immunotherapy against PD-L1-positive cancer cells.

[91], melanoma [92] and lung cancer cells [93], while quercetin
induces apoptosis in cervical carcinoma [94], colon cancer [95] and
lymphoma cells [96]. Similarly, many tannins, such as EGCG, have been
described to be cytotoxic to ovarian [97] and breast [98] cancer cells,
and many extracts rich in polyphenols also show cytotoxic activities
[99,100]. Hence, further studies should be performed to investigate
the possible immunogenic potential of a large number of polyphenols.
In cellular models of cancer, effective concentrations of polyphenols to
shown an antitumoral effect are usually high ranging from 80 to 200
μM, that concentration to modulate NK activity which are usually
lower ranging from 10 to 60 μM, suggesting a pleiotomism between
these actions induced by polyphenols for each cells, which could
exhibit implication in clinical approaches.
Other studies have reported the optimization of combinations of
polyphenols to improve the efficacy of cancer vaccines in preclinical
and clinical studies. Kang et al. [101] evaluated the potential of EGCG
to increase DNA vaccination protection in a murine skin tumor model
established with HPV-16 E7-expressing TC-1 cells. For this cancer
vaccine, the gene lysosomal-associated membrane protein 1 (LAMP-
1) represented an effective means of delivering DNA directly into APCs
in the skin and thus allowing T cell activation. The combination of
EGCG and DNA vaccination led to an enhanced tumor-specific T cell-
mediated immune response and improved antitumor effects, resulting
in a higher cure rate than either immunotherapy or EGCG alone. Lu et
al. [102] created a formulation of curcumin in micelles and
administered it to mice challenged with the B16F10 melanoma cell
line, which resulted in decreases in IL-6 and chemokine C-C motif
ligand 2 levels and enhancements in TNF-α and IFN-γ levels. More
importantly, curcumin enhanced the vaccine activity of a peptide
derived from a tumor-associated antigen (Trp2), resulting in strong
tumor inhibition compared with either the Trp2 vaccine or curcumin
alone, which showed slight tumor inhibition. These studies suggest
further perspectives for polyphenols combined with cancer vaccina-
tion approaches.
3.3. Polyphenol activation of Th1/CD8+ T cell-mediated immunity
Recent studies have reported that polyphenols exert cytotoxic
effects by activating antitumor immunity. Chen et al. [100] investi-
gated the effects of resveratrol on the renal carcinoma microenviron-
ment and found a switch from the expression of Th2 cytokines, such as
IL-4 and IL-10, to the expression of Th1 cytokines with predominance
of IFN-γ and increased infiltration of tissues by activated CD8+ T cells.
In addition, cytotoxicity was found to be increased via the up-
regulation of perforin, granzyme B and FasL expression, concomitant
with the up-regulation of Fas expression on tumor cells. Lin et al. [103]
demonstrated that rutin, a flavonoid compound, resulted in reductions
in tumors in the liver and spleen established by injection of a murine
myelomonocytic leukemia cell line (WEHI-3) into BALB/c mice and
increases in the expression of markers of adaptative immunity, CD3
and CD19, in peripheral cells after treatment. Although CD11b/
integrin and Mac3 (macrophage surface glycoprotein) expression
was decreased, macrophage phagocytosis increased in the rutin-
treated group. Additionally, Oršolić et al. (77) studied the effect of
caffeic acid by Ehrlich ascites tumors (EAT) cell inoculation in male
Swiss albino mice. After caffeic acid administration, increases in the
levels of the cytokines IL-2, IL-12 and IFN-γ and decreases in the levels
of IL-4 and IL-10 were found.
Chang et al. [104] and Bergman et al. [33] investigated the effects of
polyphenols on cocultures of PBMCs and cancer cell lines. In the first
study, the authors showed that linalool and p-coumaric acid stimulated
the production of proinflammatory cytokines, such as IFN-γ, IL-12 p40, IL-
1β and TNF-α, and cell–cell interaction markers, such as CD40-ligand and
CD40, when used to stimulate lymphocytes from healthy donors in
cocultures with the tumor cell line A549 (lung), T-47D (breast), SW-620
(colon) or Hep G2 (liver). These results suggest the capacity of phenolic
compounds to induce an adequate Th1 response. In the second study, the
authors observed that the combination of PBMCs, resveratrol and
colorectal cells resulted in the induction of apoptosis in cancer cell lines
8 J.T.G. de Carvalho et al. / Journal of Nutritional Biochemistry 85 (2020) 108428
but had variable effects on the cytokine response, whereas the
combination of PBMCs and HT29 cells resulted in decreased cytokine
levels in the presence of resveratrol. The effects on cytokine production
varied in a dose-dependent manner for RKO cells cocultured with PBMCs.
In the presence of different resveratrol concentrations, the levels of IL-1β,
IFN-γ and IL-10 generally dropped, but low resveratrol doses stimulated
TNF-α expression, while higher doses greatly reduced this expression.
These results suggest that the effects of polyphenols depend on the
dosage and the cancer type. Therefore, further conclusive details are
required to evaluate the dose–response effects of polyphenols.
3.4. Polyphenols suppress Treg activation and function
Other studies have demonstrated that polyphenols, such as
curcumin, induce cancer immunity, which is related to the suppres-
sion of Treg function and activation. Zou et al. [105] evaluated the
effect of treatment for 2 weeks on lung cancer patients. After therapy,
an increase in IFN-secreting Th1 cells and suppression of Tregs were
observed. Xu et al. [106] similarly evaluated the effect of treatment for
2 weeks on colon carcinoma patients and demonstrated a reduction in
the frequency of Treg cells, while the frequency of T effector (Foxp3−)
cells was increased. Another clinical study evaluated the effect of an
EGCG-rich extract from green tea on chronic lymphocytic leukemia
patients. The extract induced decreases in the circulating lymphocyte
and Treg cell levels, usually observed in these patients, and reductions
in the circulating levels of IL-10 and TGF-β [107].
Interestingly, pleiotropic effects have been observed for phenolic
compounds. In a melanoma establishment model, Lasso et al. [86]
observed decreases in IL-10 production and FoxP3 expression
following treatment with P2Et, but in contrast, under nontumor
conditions, an increase in the Treg frequency was seen in vivo in
healthy BALB/c or C57BL/6 mice given the same treatment. In fact,
Wong et al. [108] demonstrated the induction of regulatory T cells by
the green tea-derived polyphenol EGCG. These results suggest that the
effects of polyphenols also depend on other factors, such as the
activation state of target cells (e.g., basal versus primed) and their
microenvironment (e.g., healthy versus cancer cells). In addition, it is
important to note that a phenolic compound, such as EGCG, may have
clinical applicability in the treatment of cancer and inflammatory
disease, which were, until now, believed to be antagonistic target
interactions, and investigations to elucidate these opposing activities
might reflect a new advance in the understanding of the pathophys-
iology of these diseases.
Another important aspect that remains unknown is whether
polyphenols can modulate CTLA-4 expression in naïve T cells. To
date, there have been no studies that address this question. Based on
studies of an inflammatory model, Sharma et al. [109] demonstrated
down-regulation of CD28 and CD80 expression and up-regulation of
CTLA-4 expression by curcumin. However, as described above, the
immune regulation mediated by polyphenols is dependent on the
microenvironment, and further studies in cancer cell models should be
carried out.
3.5. PD/PD-L1 checkpoint modulation by polyphenols
Recent studies have evaluated the ability of polyphenols to affect
the expression of PD-L1 in cancer cells. Xu et al. [110] observed
suppression of PD-L1 expression in human melanoma cells (A375,
A2058 and RPMI-7951) treated with curcumin and apigenin. In
addition, they found that treatment of cocultures (A375 cells or Jurkat
cells) with these flavonoids potentiated T cell-mediated melanoma
cell killing. Taken together, these results suggest that curcumin and
apigenin may become an alternative therapeutic approach for
immune checkpoint blockade.
Other studies have evaluated the ability of polyphenols to
synergize with immunotherapy. Shao et al. [111] found that a
combination of an anti-PD-L1 antibody and bisdemethoxycurcumin
resulted in a reduction in tumor volume and increased survival in an in
vivo mouse model of bladder cancer that was established via
intravenous injection of MB49 tumor cells. Moreover, bisdemethoxy-
curcumin increased the antitumoral activity of CD8+ T cells by
reducing PD-1 expression, which was accompanied by elevated levels
of IFN-γ and granzyme B release from CD8+ cells. Zhang et al. [90]
observed that resveratrol in combination with an anti-PD-1 antibody
in a model of ovarian carcinoma greatly inhibited tumor growth, while
depletion of CD8+ T cells restored tumor progression.
In contrast, Lucas et al. [112] found enhanced expression of PD-L1
induced by treatment with resveratrol and piceatannol in the triple-
negative breast cancer cell line Cal51 and in the colon cancer cell line
SW620. The authors hypothesized that the induction of PD-L1
expression in tumor cells can sensitize the tumor cells to improve
the response to PD-L1 blockade. However, whether resveratrol and/or
piceatannol intake produces positive outcomes in combination with
PD-L1 blockade remains unclear because an increase in PD-L1
expression may also impair host T cell-mediated immunity. Thus, to
address this hypothesis, whether there is an absence of up-regulated
PD1 expression induced by these polyphenols in T cells needs to be
investigated.
The duality of polyphenols claims special attention in regard to the
in vivo intake of dietary supplements (including natural extracts),
which are widely used among patients with cancer to reduce side
effects. Whereas some authors have reported down-regulation of PD-
L1 expression by polyphenols, indicating that the use of polyphenols
together with PD-L1 blockade therapy could be antagonistic, others
have demonstrated the inverse effect, specifically that polyphenols
can enhance the immune escape of tumor cells and thus act as
protumor agents. Hence, further preclinical studies should investigate
the effect of polyphenols on PD-L1 expression in other cell lines to
confirm the opposing effects of polyphenols before clinical use in
patients.
3.6. Polyphenols suppress TAMs
Recent works have investigated the ability of polyphenols to
suppress the M2-like polarization of TAMs. Sun et al. [113]
demonstrated that M2 polarization induced by lung cancer cells was
inhibited by resveratrol. Additionally, an inhibitory function was
observed in lung cancer cells cocultured with human macrophages. In
addition, Kimura et al. [114] found that resveratrol suppressed the
formation of new lymphatic vessels (similarly to angiogenesis) by
lymphatic endothelial cells via inhibition of the production of IL-10,
monocyte chemoattractant protein-1 and VEGF in M2 macrophages.
Jang et al. [115] investigated the effect of EGCG on Balb/c tumors
induced by the murine breast cancer cell line 4T1. There were a
decrease in the level of CCL-2 and a reduction in the infiltration of
TAM-like M2 macrophages. These effects were associated with the up-
regulation of microRNA-16 (miR-16) expression in tumor cells via
exosomes. Mukhereej et al. recently formulated liposomes with
curcumin, EGCG and resveratrol. They treated mice with tumors
derived from glioblastoma cells (GL261) [116] or TC-1 cells infected
with HPV [117]. As a result, they observed reduced tumor growth in
both studies, as well as modification of the phenotype of TAMs, which
switched from the M2 phenotype marked as higher expression of
arginase and IL-10 to the M1 phenotype identified by higher
expression of and lower expression of inducible nitric oxide synthase
(iNOS) and IL-12.
Guruvayoorappan and Kuttan [118] evaluated the antiangiogenic
activity of rutin by monitoring in vivo B16-F10 melanoma cell-induced
capillary formation in C57BL/6 mice. The administration of rutin
 J.T.G. de Carvalho et al. / Journal of Nutritional Biochemistry 85 (2020) 108428
significantly inhibited (43.35%) the number of tumor-directed
capillaries, which was accompanied by reductions in the levels of
VEGF and IL-1β and an increase in the level of TNF-α.
Oršolić et al. [119] studied the effect of caffeic acid on Ehrlich
ascites tumors induced by EAT cell inoculation in male Swiss albino
mice. Caffeic acid administration produced a significant decrease in
tumor growth and increased the life span of the mice by 28.39%. The
effect on macrophage polarization was evidenced by decreased Arg1
activity in splenic and peritoneal macrophages and an increased
percentage of macrophages in the peritoneum. In addition, there was
significant inhibition of neovascularization and the VEGF level in the
peritoneal fluid after caffeic acid administration. These studies suggest
that some polyphenols suppress M2 polarization, inhibiting tumor
progression and metastasis.
4. Bioavailability of polyphenols
Large numbers of studies mentioned above have demonstrated
that polyphenols have immunoregulatory effects on cancer microen-
vironment. Most of these biologic studies have been conducted in
vitro, i.e., utilizing cultured cells, which could not reflect the same
effect when expanded to clinical use in human patients. Even though a
compound has strong activities in vitro, it would have little biological
activity in vivo if little or none of the compound gets to the target
tissues [120]. A major reason for the in vitro/in vivo discrepancies may
be the lack of bioavailability of polyphenols in vivo, in particular after
oral administration [121,122]. Large studies follow the general
directions for improving bioavailability of polyphenols by generation
of analogs using nanostructure-based drug delivery system, lipid-
based carriers and others [120].
Another parameter that should be taken into account in in vitro
studies is if the test substance is appropriate. The most amounts of
dietary polyphenols exist in food as aglycones or glycosides. In
glycosides forms, the polyphenols cannot be absorbed and must be
hydrolyzed by the intestinal enzymes or by the colonic microflora
before absorption [121,123]. After absorption, they reach the liver
where they may be further subjected to extensive first-pass phase II
metabolism (including glucuronidation, methylation, sulfation or a
combination of these), resulting in a series of metabolites derivatives
[121,122]. All these modifications deeply affect the biological activity of
polyphenols. Consequently, the compounds that reach cells and tissues
are chemically, biologically and, in many instances, functionally
different from the original dietary form [124]. Often, the compounds
tested were polyphenol aglycones or their sugar conjugates rather than
their active metabolites. Thus, many investigators tested the wrong
compound when trying to unravel which physiological mechanisms
were involved in the health effects of the polyphenols.
To avoid these problems, the best choice to do is on in vivo
experiments. As far as animal studies are concerned, they provide
extremely valuable information and overcome some of the difficulties
associated with in vitro studies utilizing cell culture. However,
differences between the human and animal may also lead to potential
problems of extrapolation. For example, some metabolites generated
in rodents were not present in humans [125].
Thus, future preclinical studies should be conducted considering all
these factors, such as bioactive metabolite interference, the use of
analogues with better bioavailability profile or formulations with
better bioavailability in conjunction with the use of animal models.
5. Conclusion
Different mechanisms support the antitumor and immunoregula-
tory effects of polyphenols, including the suppression of immune
escape mechanisms (Tregs and PD-L1), TAM suppression and
adaptative immune activation (memory). From an efficacy and safety
9
point of view, the data are still inconclusive, and further preclinical
studies should be performed before beginning clinical use in patients.
We propose that future studies investigate PD-1 expression in T cells,
CTLA-4 expression in naïve T cells, interactions with immunotherapy,
the mechanism underlying pleiotropism (cancer versus inflamma-
tion) and dose responsiveness in different cancer lines and immune
cells with a special focus on resveratrol, curcumin and EGCC since
more data are available for those compounds. In addition, further
studies for improve the bioavailability profile of polyphenols com-
pounds are essentials to clinical use. Together, these data could clarify
the role of polyphenols in cancer immunity to more precisely define
the potential of the clinical application of polyphenols in immuno-
oncology.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Acknowledgments
This work was supported by grants from Universidade Federal da
Grande Dourados (UFGD); Fundação de Apoio ao Desenvolvimento do
Ensino Ciência e Tecnologia do Estado de Mato Grosso do Sul (FUNDECT);
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES);
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
and Financiadora de Estudos e Projetos (FINEP).
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