cancers

Review
The Tumor Microenvironment as a Therapeutic Target
in Cutaneous T Cell Lymphoma
Louis Boafo Kwantwi 1,2,3 , Steven T. Rosen 2,4 and Christiane Querfeld 1,2,4,5, *

1 Department of Pathology, City of Hope Medical Center, Duarte, CA 91010, USA; [email protected]
2 Beckman Research Institute, Duarte, CA 91010, USA; [email protected]
3 Department of Anatomy and Neurobiology, College of Medicine, Northeast Ohio Medical University,
Rootstown, OH 44272, USA
4 Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center,
Duarte, CA 91010, USA
5 Division of Dermatology, City of Hope Medical Center, Duarte, CA 91010, USA
* Correspondence: [email protected]

Simple Summary: Cutaneous T cell lymphomas (CTCLs) are a group of rare lymphoproliferative
malignancies manifesting in the skin. Cutaneous T cell lymphomas are an incurable, disfiguring,
and life-threatening disease. Emerging studies have implicated the surrounding cells of malignant
T cells (tumor microenvironment) in the disease evolution. This has revealed that targeting the tumor
microenvironment has therapeutic potential in cutaneous T cell lymphomas. This review provides a
detailed insight into the contribution of the tumor microenvironment in cutaneous T cell lymphomas
and the targeting strategies.

Abstract: Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lym-
phomas, with mycosis fungoides and Sézary syndrome being the two common subtypes. Despite
the substantial improvement in early-stage diagnosis and treatments, some patients still progress
to the advanced stage with an elusive underpinning mechanism. While this unsubstantiated dis-
ease mechanism coupled with diverse clinical outcomes poses challenges in disease management,
emerging evidence has implicated the tumor microenvironment in the disease process, thus revealing
Citation: Kwantwi, L.B.; Rosen, S.T.; a promising therapeutic potential of targeting the tumor microenvironment. Notably, malignant
Querfeld, C. The Tumor
T cells can shape their microenvironment to dampen antitumor immunity, leading to Th2-dominated
Microenvironment as a Therapeutic
responses that promote tumor progression. This is largely orchestrated by alterations in cytokines
Target in Cutaneous T Cell
expression patterns, genetic dysregulations, inhibitory effects of immune checkpoint molecules, and
Lymphoma. Cancers 2024, 16, 3368.
immunosuppressive cells. Herein, the recent insights into the determining factors in the CTCL tumor
https://doi.org/10.3390/
cancers16193368
microenvironment that support their progression have been highlighted. Also, recent advances
in strategies to target the CTCL tumor micromovement with the rationale of improving treatment
Academic Editor: Jose Manuel
efficacy have been discussed.
Lopes

Received: 1 September 2024 Keywords: mycosis fungoides; Sézary syndrome; tumor microenvironment; cutaneous T cell lym-
Revised: 27 September 2024 phoma; cytokines; immune checkpoints; genetic alterations
Accepted: 28 September 2024
Published: 1 October 2024

1. Introduction
Copyright: © 2024 by the authors.
Cutaneous T cell lymphomas are a rare form of non-Hodgkin lymphomas character-
Licensee MDPI, Basel, Switzerland. ized by the accumulation of malignant CD4+ lymphocytes homing into the skin [1]. Even
This article is an open access article though the etiology is still an enigma, the highest incidence rates are found in African
distributed under the terms and American and aged populations with a four-fold increase in individuals over 70 years [2,3].
conditions of the Creative Commons Although it is a heterogenous disease, mycosis fungoides (MF) and Sézary syndrome (SS)
Attribution (CC BY) license (https:// account for 60% of all cases, making them the most studied and common subtypes [4]. MF
creativecommons.org/licenses/by/ is defined by patches, plaques, tumors, and/or erythroderma, while SS is a more aggressive
4.0/). and leukemic form of CTCLs characterized by erythroderma and the presence of clonally

Cancers 2024, 16, 3368. https://doi.org/10.3390/cancers16193368 https://www.mdpi.com/journal/cancers

Cancers 2024, 16, 3368 2 of 18

similar neoplastic T cells with cerebriform nuclei (Sézary cells) in the peripheral blood,
skin, and/or lymph nodes [5,6]. The heterogeneous presentation not only makes a defini-
tive diagnosis of CTCLs often difficult but also the selection of appropriate therapeutic
options [7]. Although efforts made to understand the pathophysiology of CTCLs have led
to the development of new treatment modalities for the early stage [8] and advanced stage
of the disease [9–11], most patients develop progressive disease due to treatment failure,
which makes our knowledge of the exact molecular mechanisms underpinning the disease
incomplete. Given the reduced survival rates together with the increasing aggressiveness
of CTCLs, studies to map the underlying mechanisms have pinpointed the critical role of
the CTCL tumor microenvironment (TME) in the disease processes. Notably, the interaction
between malignant T cells and their niche via cytokines dysregulations, genetic alterations,
and immune cells infiltrating the microenvironment have become crucial determinants in
tumor initiation, metastasis, therapeutic resistance, and other hallmarks of CTCLs [1,12,13].
Therefore, this review aims to elucidate the molecular interaction between CTCLs and their
microenvironment and evaluate how such an interaction affects the fate of malignant T cells.
In addition, insights into the recent advances in strategies to target the TME are highlighted.

2. Role of CTCL Tumor Microenvironment in CTCL Progression

The CTCL TME is composed of malignant T cells, endothelial cells, fibroblast, ker-
atinocytes, and immune cells, including macrophages, monocytes, B cells, neutrophils, mast
cells, eosinophils, natural killer cells, dendritic cells, T cells, myeloid-derived suppressor
cells, and regulatory T cells [1,14,15]. The cellular communication mediated by tumor-
derived factors alters the physiological role of antitumor immune cells, which shields
CTCL cells from therapeutic agents, hence promoting their progression. Notably, the
hostile nature of the TME, which is partly attributed to hypoxia [16], causes endothelial
cells in the CTCL TME to proliferate and form new vessels, thereby promoting tumor
progression [17,18]. Moreover, malignant T cells also activate stem cells and epithelial-
to-mesenchymal transition to support their continuous renewal and differentiation [12].
Hence, the microenvironmental niche of CTCLs contributes to all facets of the disease
processes, including immunosuppression [19–21], therapeutic resistance [22,23], apoptosis
resistance [21,24–27], invasion and migration [28–31], angiogenesis [17,18,32], and tumor
proliferation [33–36].

2.1. The Immune Tumor Microenvironment and CTCL Progression

2.1.1. Macrophages
Macrophages are one of the major leukocytes infiltrating the tumor microenvironment.
Depending on the prevailing conditions in the TME, macrophages can be polarized into
M1 and M2 phenotypes. Functionally, tumor-associated macrophages (TAMs) designated
as M1 exhibit pro-inflammatory and antitumor functions, while M2 macrophages are anti-
inflammatory with tumor-promoting functions [37]. Indeed, it has been found that while
the early stage of MF is characterized by the high infiltration of M1 macrophages, M2
macrophages predominate in advanced tumors [38]. In the large cell transformation of
MF, miR-708 downregulation and upregulation of miR-146a and miR-21 were associated
with the infiltration of M2 macrophages, suggesting their immunosuppressive role in the
TME [39]. Furthermore, both CD68+ and CD163+ macrophages are associated with the
advanced stage of CTCLs [40,41].
In several mechanistic studies, macrophages polarized by CTCL TME tend to sup-
port CTCL progression through the expression of cytokines and growth factors [42–45].
For example, inflammatory cytokines, including CXCL5, CCL13, and IL10, produced by
periostin-induced TAMs were found to create an immunosuppressive tumor microenvi-
ronment, leading to MF development [42]. Furthermore, M2 macrophage cocultured with
CTCL cells upregulated S100A9/TLR4 via NF-kB to induce apoptosis resistance, leading
to CTCL progression [19]. More recently, Han et al. showed that PD-1+ M2 macrophages
induced by CTCL TME through the NF-kB/STAT/JAK pathway can impair the phagocytic
 Cancers 2024, 16, x FOR PEER REVIEW 3 of

Cancers 2024, 16, 3368 3 of 18

CTCL cells upregulated S100A9/TLR4 via NF-kB to induce apoptosis resistance, leadi
to CTCL progression [19]. More recently, Han et al. showed that PD-1+ M2 macrophag
induced by CTCL TME through the NF-kB/STAT/JAK pathway can impair the phagocy
activity of macrophages, promoting CTCL growth [46]. Macrophages are also important
activity of macrophages, promoting CTCL growth [46]. Macrophages are also importa
drivers of angiogenesis in CTCLs, as described by Wu et al. [47]. The depletion of M2-like
drivers of angiogenesis in CTCLs, as described by Wu et al. [47]. The depletion of M2-li
TAMs delayed CTCL development in xenograft mouse models, supporting their role in
TAMs delayed CTCL development in xenograft mouse models, supporting their role
CTCL tumorigenesis [47].
CTCL tumorigenesis [47].
Regarding monocytes, evidence
Regarding suggests
monocytes, that malignant
evidence suggests Tthat
cells can recruit
malignant monocytes
T cells can recruit mon
via a CCL5-dependent manner to promote the survival of CTCL cells [48]. Furthermore,
cytes via a CCL5-dependent manner to promote the survival of CTCL cells [48]. Furthe
monocytes can interact with malignant
more, monocytes T cellswith
can interact to promote immunosuppression
malignant and CTCL
T cells to promote immunosuppression a
progression [19], CTCL
as shown in Figure
progression 1. as shown in Figure 1.
[19],

Figure
Figure 1. CTCL TME 1. CTCLregulates
negatively TME negatively regulates
the tumor immunethe tumor immune microenvironment
microenvironment to support CT
to support CTCL
progression. Immune cells infiltrating the CTCL tumor microenvironment promote angiogenes
progression. Immune cells infiltrating the CTCL tumor microenvironment promote angiogenesis,
tumor growth, migration, and immunosuppression.
tumor growth, migration, and immunosuppression.
2.1.2. Mast Cells
2.1.2. Mast Cells
Mast cells infiltrating the CTCL TME have been established as key players in the d
Mast cells infiltrating the CTCL TME have been established as key players in the dis-
ease processes. In CTCL lesions, increased mast cells not only show a positive relationsh
ease processes. Inwith
CTCL lesions, increased mast cells not only show a positive relationship
tumor stage but also microvessel density, suggesting their role in inducing ang
with tumor stage genesis.
but alsoIn microvessel
support of density, suggesting
this, delayed their role
tumor growth wasin found
inducingin aangiogene-
cutaneous lymphom
sis. In support of mouse
this, delayed
model deficient in mast cells [49]. In MF, a high number of mastmouse
tumor growth was found in a cutaneous lymphoma cells and trypta
model deficient in aremast cells
drivers [49].and
of itch In MF
MF,disease
a highseverity
number of In
[50]. mast cells and
contrast, Edertryptase arehigher ma
et al. found
drivers of itch and MF disease severity [50]. In contrast, Eder et al. found higher mast cells
cells in clinical stage IA and IB patients than in the IIA and IIB stages [51], suggesting th
in clinical stage IA and IB
a higher patients
number thancells
of mast in the
mayIIA and
not IIB stages
necessarily [51],the
reflect suggesting that a
stage of CTCLs.
higher number of mast cells may not necessarily reflect the stage of CTCLs.

2.1.3. Eosinophils and Neutrophils

Eosinophils and neutrophils are important components of innate cells with key roles
in host defense mechanisms. However, signals within the TME can alter their physiology to
support tumor progression [52–55]. Studies have shown that a high density of eosinophils
either in blood [56] or skin lesions is associated with the aggressiveness of the disease [14,56].
Cancers 2024, 16, 3368 4 of 18

Similar to other innate immune cells, the activation of eosinophils drives inflammation in
CTCLs to accelerate disease progression [14,57]. In a study aimed at elucidating eosinophils-
activating factors in CTCL TME, IL5 and high mobility BOX-1 protein (HMGB1) expressed
by malignant T cells were identified as key activators of eosinophils in MF [58]. Moreover, a
high infiltration of neutrophils mediated by IL17 and IL8 is linked with MF and SS disease
progression [59,60].

2.1.4. Dendritic Cells and Natural Killer Cells

Dendritic cells (DCs) are the most efficient antigen-presenting cells noted for capturing
and presenting antigens to naïve T cells [61]. Dendritic cells can exhibit both anti-tumor and
protumor functions depending on the prevailing conditions within the TME [61]. Whereas
mature dendritic cells play antitumor functions, immature dendritic cells foster immune
tolerance, thus promoting tumor progression [62]. Berger et al. cocultured immature
dendritic cells with CTCL cells from SS patients and found that immature dendritic cells can
sustain the growth of CTCLs [63]. Furthermore, DCs can promote the migration of SS and
MF cells [64]. OX40 is a costimulatory signal that promotes T cell expansion and survival. In
a recent study, the activation of benign T cells by OX40L+CD40L+ dendritic cells stimulated
inflammation and the release of tumorigenic signals to CTCLs [65]. Natural killer cells (NKs)
are lymphoid members of the innate immune system playing cytotoxic functions similar
to CD8+ T cells. In CTCLs, malignant T cells from SS patients can reduce CD16+CD56dim
NK cells and downregulate NKG2D, the main activator of antitumor activity in NK cells,
to promote their escape from NK-induced antitumor immunity [66]. Additionally, the
increased expression of NK cell receptor KIR3DL2 has been found in MF [67].

2.1.5. Myeloid-Derived Suppressor Cells (MDSCs)

MDSCs represent a heterogeneous population of immune cells implicated in many
pathologic conditions, including cancers [15,68]. In CTCLs, MDSC accumulation is linked
with worse clinical outcomes in patients [69] and the advanced stage of SS and MF [70].
Furthermore, MDSCs have been shown to express high levels of arginase and nitric ox-
ide (NO) to potentiate immunosuppression and CTCL progression [20]. Maliniemi et al.
showed that CD33+ myeloid suppressor cells express indoleamine 2,3-deoxygenase 1, an
immune checkpoint molecule, supporting their role in immunosuppression [71].

2.1.6. Tumor-Infiltrating Lymphocytes

Tumor-infiltrating lymphocytes are composed of heterogeneous immune cells with
the primary function of clearing tumor cells. However, immunosuppressive factors in
the TME hampers their function to facilitate tumor escape and progression [72]. Largely,
markers associated with T cell exhaustion, including PD-1, CTLA-4, LAG-3, TIGIT, and
TIM-3 [73,74], have been shown as crucial players in cancer-mediated immunosuppression
in CTCLs. Furthermore, emerging evidence shows that microbiota present in CTCL TME
can negatively regulate antitumor immunity, as demonstrated by Blümel et al. [75]. Here,
authors established that staphylococcal alpha-toxin can promote the escape of CTCL cells
from CD8+ T cell-mediated killing, hence facilitating SS progression [75]. Additionally, the
cytotoxic functions of lymphocytes can be impaired through CTCL-mediated inhibition
of cytokines involved in T cell priming. For example, SS cells can attenuate the cytotoxic
functions of CD8+ T cells by suppressing their responsiveness to IL10 [76]. Furthermore,
Zhen et al. have established that increased expression of miR-155, -130, and -21 in Hut78
and Myla cell lines can induce CD8+ T cell exhaustion, leading to CTCL progression [77].
B cells infiltrating the CTCL tumor microenvironment contribute to the pathophys-
iology of the disease. It has been shown that there is a high infiltration of B cells in MF
patients compared to healthy controls [78]. Additionally, the high infiltration of B cells
correlates positively with MF progression [78]. Functionally, B cells in the MF tumor mi-
croenvironment release immunosuppressive cytokines, contributing significantly to tumor
cell growth, dissemination, angiogenesis, and immunosuppression [13].
Cancers 2024, 16, 3368 5 of 18

2.1.7. Regulatory T Cells

In MF, Tregs have diverse functions with contrasting roles having been reported.
While the early patch stage of MF is associated with high Treg numbers, a low number of
FOXP3+ cells are found in the advanced stage [16,79–81]. Indeed, the reduced expression
of FOXP3+ cells relative to CD3+ T cells in the early stages of MF correlates with the
disease progression [82]. On the contrary, a high infiltration of Tregs correlates with
good clinical outcomes in MF patients [82]. In SS, IL10 and TGF-β secreted by Tregs can
suppress the secretion of IL2 and IFN-γ and maintain DC immaturity, leading to CTCL
proliferation [83]. Similarly, high Tregs(CD4+ CD25+) in SS patients have been found to
suppress the proliferation of autologous CD4+ CD25- responder T cells [20].
Evidence has shown that the microbiota in CTCL TME can augment the tumor-
promoting functions of Tregs [84]. According to Willerslev-Olsen et al. Staphylococcus
aureus enterotoxins (SEA) can induce FOXP3 expression in malignant SS cells via the STAT5
pathway [84].

2.2. Role of Cancer-Associated Fibroblasts in CTCL

Cancer-associated fibroblasts (CAF) are major components of the TME known to poten-
tiate the immune escape of tumor cells [85,86]. In CTCLs, CAF can modulate the expression
of biomarkers associated with CTCL pathogenesis, attenuate Th1-related cytokines, and
promote the Th2-dominant microenvironment, leading to CTCL progression [87,88]. For
example, MF cells were found to induce normal fibroblast to express high levels of TWIST1
and16,TOX
Cancers 2024, x FOR and Th2 markers, such as GATA3, IL6, and IL4 but low levels of Th1 markers,
PEER REVIEW 6 of 19
IFNG and TBX2 [87] (Figure 2).

Figure 2. Role of cancer-associated fibroblasts in CTCLs. Cancer-associated fibroblasts promote

Figure 2. Role of cancer-associated
CTCL migration,fibroblasts in CTCLs.
growth, apoptosis Cancer-associated
resistance, fibroblasts promote CTCL
and immunosuppression.
migration, growth, apoptosis resistance, and immunosuppression.
Data have shown that chemokines secreted by CAF can potentiate their tumor-pro-
motingthat
Data have shown functions [22,29,89]. Specifically,
chemokines secreted by CAF-induced
CAF canCXCR4/SDF
potentiate promoted SS cell mi-
their tumor-
gration by downregulating CD26/dipeptidyl peptidase IV [29]. Relatedly, eotaxins de-
promoting functions [22,29,89]. Specifically, CAF-induced CXCR4/SDF promoted SS cell
rived from dermal fibroblast can interact with CCR3+ lymphocytes to promote CTCL de-
migration by downregulating CD26/dipeptidyl peptidase IV [29]. Relatedly, eotaxins
velopment [89]. Furthermore, CXCL12/CXCR4 secreted by MF-derived CAF was found to
derived from dermal fibroblast
protect malignantcan interact
T cells with CCR3+ lymphocytes
from doxorubicin-induced to promote
apoptosis, thereby CTCL
enhancing the mi-
development [89]. Furthermore, CXCL12/CXCR4
gration of MF cells [22]. Beksac et al.secreted by MF-derived
also cocultured fibroblast andCAF was found
malignant MF cells
isolated
to protect malignant from
T cells the doxorubicin-induced
from skin of early-stage CTCLsapoptosis,
and found that fibroblast
thereby can enhance
enhancing thethe
proliferation of MF cells [33].

2.3. Role of Vascular or Endothelial Cells in CTCLs

Angiogenesis, characterized by vascular or lymphatic vessel formation, is an im-
portant process for tumor dissemination [90–92]. Several molecular and correlative stud-
ies have detailed the indispensable role of endothelial cells and their related markers in
Cancers 2024, 16, 3368 6 of 18

migration of MF cells [22]. Beksac et al. also cocultured fibroblast and malignant MF cells
isolated from the skin of early-stage CTCLs and found that fibroblast can enhance the
proliferation of MF cells [33].

2.3. Role of Vascular or Endothelial Cells in CTCLs

Angiogenesis, characterized by vascular or lymphatic vessel formation, is an impor-
tant process for tumor dissemination [90–92]. Several molecular and correlative studies
have detailed the indispensable role of endothelial cells and their related markers in CTCL
pathogenesis. In MF and SS, the expression levels of VEGFR-3, VEGF-C, and other an-
giogenic markers, such as CD31, podoplanin, and LYVE-1, correlate significantly with
disease progression [93–96]. Besides tissue expressions, serum levels of VEGF-A reflect
the severity of itching in MF and SS patients [97]. Furthermore, a positive correlation
between podoplanin expression and lymphatic vessel density in malignant T cells has been
linked to tumor aggressiveness and advanced stage of MF [98]. Moreover, intertumoral
SOX18, a marker of neovascularization, correlates with MF disease progression, cutaneous
involvement, and metastasis [28].
Mechanistically, in situ expression of LTα driven by the aberrant activation of the
JAK3/STAT5 pathway acts in an autocrine fashion via TNF-alpha receptor 2 to induce IL6
Cancersexpression
2024, 16, x FORin malignant
PEER REVIEW T cells, which together with VEGF induce tube formation and endothe- 7 of 19
lial cell sprouting [18]. According to Lauenborg et al. IL17F derived from Myla supernatant
can stimulate angiogenesis through tube formation and sprouting to facilitate CTCL progres-
sion [17]. Furthermore, supernatant
placentalcangrowth
stimulatefactor
angiogenesis
(PlGF) through tube formation
and VEGF-A and sprouting
expressed in CTCLto facilitate
skin
CTCL progression [17]. Furthermore, placental growth factor (PlGF) and VEGF-A ex-
were found to promote tumor growth via tumor vasculature formation [32]. The same study
pressed in CTCL skin were found to promote tumor growth via tumor vasculature for-
found serum levels of PIG4
mation to The
[32]. correlate withfound
same study MF/SS serumdisease severity,
levels of suggesting
PIG4 to correlate a possible
with MF/SS disease
utility of PIG4 eitherseverity,
as a biomarker
suggestingor potential
a possible therapeutic
utility target
of PIG4 either as a[32]. Additionally,
biomarker VEGFR-
or potential therapeu-
3 expressed in CTCL ticcell lines
target [32]. and a xenograft
Additionally, VEGFR-3mouse model
expressed of MF
in CTCL cellexhibited a protective
lines and a xenograft mouse
model of MF exhibited
effect towards the suberoylanilide a protective
hydroxamic effect
acid towards the suberoylanilide
(SAHA)-mediated hydroxamic
inhibition of tumor acid
(SAHA)-mediated inhibition of tumor cells, hence promoting tumor progression [23], as
cells, hence promoting tumor progression [23], as shown in Figure 3.
shown in Figure 3.

Figure 3. Contribution of endothelial cells to CTCLs. Endothelial cells promote angiogenesis, tumor
Figure 3. Contributionmetastasis,
of endothelial
growth, cells to CTCLs.
and apoptosis Endothelial cells promote angiogenesis, tumor
resistance.
metastasis, growth, and apoptosis resistance.
3. Molecular Mechanisms of CTCL Immune Evasion
Immune evasion of CTCLs involves several mechanisms, including the secretion of
immunosuppressive factors, such as cytokines and exosomal cargos, genetic alterations,
immune checkpoint-mediated T cell inhibition, and apoptosis resistance, as shown in Fig-
ure 4.
Cancers 2024, 16, 3368 7 of 18

3. Molecular Mechanisms of CTCL Immune Evasion

Immune evasion of CTCLs involves several mechanisms, including the secretion of
immunosuppressive factors, such as cytokines and exosomal cargos, genetic alterations,
Cancers 2024, 16, x FOR PEER REVIEW 8 of 19
immune checkpoint-mediated T cell inhibition, and apoptosis resistance, as shown in
Figure 4.

Figure 4. Molecular mechanisms of CTCL progression: CTCL TME influences the malignant transfor-
mation of CTCLs through genetic alterations, apoptosis resistance, immune checkpoint-mediated
immunosuppression, cytokine dysregulations, and exosome secretions.

3.1. Apoptosis Resistance

Apoptosis evasion is a hallmark of cancer progression. This process is characterized
by a decrease in the function of pro-apoptotic proteins and/or an increase in anti-apoptotic
proteins. They can block cell death signals, hence promoting apoptosis resistance [99]. Fas
ligand (FasL) expressed on cytotoxic T cells plays an important role in the Fas-mediated
killing of tumor cells. However, FasL expressed on tumor cells can counterattack the
tumor-killing abilities of tumor-infiltrating lymphocytes [100]. In support of this, Ni et al.
have found that FasL expressed by malignant T cells and epidermal keratinocytes can
induce the apoptosis of CD8+ T cells and MF progression [101]. Indeed, fewer CD8+ T cells
appear to be distributed in the vicinity of FasL-positive tumor cells.
CTCL progression is dependent on their ability to escape activation-induced cell death
(AICD) [24–27]. According to Klemke et al., malignant T cells from SS patients show re-
duced surface expression of CD95L, an apoptosis-inducing ligand, upon TCR stimulation,
leading to AICD resistance [24]. Relatedly, the overexpression of E3 ubiquitin ligase c-CBL
in CTCL cells inhibits AICD [25]. Genomic instability [102], mutations in genes [103], dys-
regulation of cytokines, and signaling pathways [104,105] are other mechanisms implicated
in apoptosis resistance in CTCLs.

Figure 4. Molecular mechanisms of CTCL progression: CTCL TME influences the malignant trans-
formation of CTCLs through genetic alterations, apoptosis resistance, immune checkpoint-mediated
immunosuppression, cytokine dysregulations, and exosome secretions.

3.1. Apoptosis Resistance

Apoptosis evasion is a hallmark of cancer progression. This process is characterized
Cancers 2024, 16, 3368 8 of 18

3.2. Cytokine Dysregulation in CTCLs

The pathophysiology of cancers is impacted considerably by the cytokine milieu of its
environment [91,106–108]. Specifically, alterations in cytokines such as IL32, IL22, IL17F,
IL17A, IL16, IL15, and HMGB1 [109,110] can create an immunosuppressive tumor microen-
vironment in CTCLs to facilitate immune evasion and tumor progression. According to
Ito et al., C-C motif chemokine ligand 20 (CCL20) induced by IL22/IL22RA1 axis interacts
with CCR6 receptor to promote migration and distant organ metastasis of CTCLs [31].
Intriguingly, increased CCL20 in clinical samples correlates positively with CTCL progres-
sion [111]. The elevated expression of 1L10 in malignant T cells facilitates tumor growth
in vivo through IL10-mediated macrophage infiltration and M2 polarization [112]. More-
over, IL10 expressed by malignant T cells can impair the differentiation of monocytes to
matured DCs, leading to antitumor suppression [113]. In a similar study, IKZF2-induced
IL10 expression in malignant T cells was found to dampen the antitumor immunity of MHC
II molecules, hence promoting apoptosis resistance and CTCL progression [21]. Indeed,
increased 1L10 expression is associated with the clinical course of MF [21,112]. Ohmatsu
et al. have indicated that the increased mRNA expression of IL32 not only predicts MF
severity but can enhance the proliferation of CTCL cells [114]. Additionally, IL32 is known
to upregulate survival genes [114,115], important for the initiation, maintenance, and pro-
gression of CTCLs [116]. IL16 and thymic stromal lymphopoietin (TSLP) expressed in the
early stages of MF not only enhances the infiltration of malignant T cells into the skin but
also contributes to CTCL proliferation [30]. The contribution of IL31 to CTCL pathogen-
esis appears to be diverse. While elevated serum levels of IL31 correlate positively with
advanced disease stage [60] and pruritus [117], Santen et al. found low levels of IL31 in
pruritic folliculotropic (FMF) but no expression in non-pruritic patients (MF) [118]. Accord-
ing to Mishra et al., the overexpression of IL15 by CD4+ T cells is associated with histone
deacetylase histone (HDAC)1/6 upregulation and miRNA-21 activation, promoting CTCL
progression [119]. Furthermore, the activation of mTORC1 by IL15 and IL2 in malignant
CD4+ T cells promoted CTCL proliferation [120]. In addition to the above, Thode et al. have
demonstrated that IL15 expressed by malignant T cells activates epidermal keratinocytes
to promote CTCL proliferation [121]. It is interesting to note that while IL15 expression in
skin-homing CD4+ T cells and peripheral blood CD4+ T cells correlated with CTCL disease
progression [119], no correlation was found between IL15 miRNA expression in malignant
T cells and CTCL advancement [122]. Additionally, IL17F induced by malignant T cells
has been shown to promote the malignant transformation of MF cells and angiogenesis in
CTCLs [17]. Senda and coworkers assessed the role of HMGB1 in CTCLs and found that
high levels of HMGB1 in skin lesions and sera are associated with increased Th2 immune
response and the induction of angiogenesis [123].

3.3. Genetic Alterations in CTCLs

Genetic alterations, including somatic mutation and mutagenic pathways, are impor-
tant regulators of several cancer types, including CTCLs [124]. Evidence indicates that p53
mutation is linked with MF progression and predicts poor survival in patients [34,125].
Consequentially, p53 mutation status has been proposed as a possible biomarker to stratify
patients at risk of advanced MF disease [125]. In a more mechanistic study, the dysregula-
tion of p53 function has been shown to protect CTCL cells from apoptosis [126,127]. Several
lines of evidence have shown that p21 dysregulation is associated with increased prolifera-
tion of CTCL cells [35,36,128,129]. Moreover, KRAS mutation promotes apoptosis resistance
and predicts poor prognosis in MF patients [130,131]. In MF and SS, disease progression
can be potentiated by alterations in CARD11 [103], TNFRSF1B [132], PLCG1 [133], and
KIT [134]. Additionally, evidence from several whole-genomic and whole-exon sequencing
studies suggests that mutation in NOTCH2 [34], TNFRSF1B, CTLA4-CD28 fusion [132],
RB1, PTEN, DNMT3A, CDKN1B [103], CARD11, CDKN2A, and CCR4 [135] can promote
CTCL progression. Although mutations in these genes are not frequently encountered
in MF and SS patients, they can serve as potential therapeutic targets for CTCL patients.
Cancers 2024, 16, 3368 9 of 18

According to McGirt et al., JAK3 mutation in MF cells can induce apoptosis resistance and
enhance CTCL proliferation [34].
Cancer-associated microbiota are important players in cancer progression [107,136,137].
In a study by Willerslev-Olsen et al., staphylococcal enterotoxin A (SEA) cocultured with
non-malignant T cells was found to activate the STAT3/JAK3 pathway and induce IL17
expression [137]. Relatedly, IL17 and IL22 induced by STAT3 hyperactivation in a bacterial-
dominated environment were found to enhance the proliferation of CTCL cells [136]. In
a genomic analysis conducted in mice and humans, genetic instability mediated by a
mutation in telomere-binding factor (TBF) was linked to CTCL development [138].

3.4. Immune Checkpoint-Mediated Suppression of T Cells

Increased expression of immune checkpoint molecules, including CTLA-4 [73],
PD-1 [21,139,140], PD-L1 [73,139,141], and ICOS [73,141], on malignant T cells corre-
lates positively with the advanced disease stage of CTCLs. Detailed insight has revealed
that PD-L1 expression in CTCL cell lines can induce M2 macrophages to promote CTCL
growth [142]. Furthermore, it has been found that increased PD-1 can impair antitumor im-
mune response and promote Th2 responses, which facilitate CTCL tumor growth [143,144].
The available evidence supports the notion that reversing T cell exhaustion is key to restor-
ing T cell function. Although this has largely been welcomed as a potential therapeutic
strategy, an integrated genomic analysis in humans and a mice model of T cell lymphomas
has found that, while the loss of PD-1 function promotes the reversal of T cell exhaus-
tion, this is associated with FOXM1-mediated transcriptional signature, leading to poor
prognostic outcomes in SS and MF patients [145].

3.5. Exosomes in CTCLs

Studies on exosomes have demonstrated their involvement in all aspects of tumorige-
nesis, including invasion and migration, angiogenesis induction, and tumor escape from
immunosurveillance [146–148]. In the CTCL context, the available evidence indicates that
miR- 155 derived from MF cell lines can enhance the migratory effect of MF cells. Inter-
estingly, plasma exosomes from MF patients enhances the migration of normal peripheral
blood mononuclear cells in a coculture system [149]. However, considering the large body
of evidence on the diverse role of exosomes in tumorigenesis across several cancer types,
further insights are required to fully understand the role of exosomes in CTCLs.

4. Advances in Strategies to Target CTCLs

The past few years have seen a great improvement in cancer treatment through a
combination of agents or drugs targeting the CTCL tumor microenvironment. Specifi-
cally, targeting immune evasion mechanisms of malignant T cells and other populations
within the TME contributing to CTCL tumorigenesis is promising. Immune checkpoint
inhibitors, including pembrolizumab, durvalumab, and ontorpacept (TTI-621; SIRPα-IgG1
Fc), have shown significant antitumor activity with durable and long-lasting responses with
manageable toxicity profiles in CTCL patients [150–154]. The intralesional application of
ontorpacept (TTI-621) has led to activity in adjacent or distal non-injected lesions, suggest-
ing systemic and locoregional abscopal effects [153]. Studies have shown that anti-PD-L1
(durvalumab), lenalidomide, and TTI-621 can re-program M2 macrophages to boost antitu-
mor functions against CTCL cells [46,142]. Furthermore, the depletion of macrophages in a
CTCL murine model using CCR2 inhibitors can synergize with anti-PD-1 to suppress tumor
growth [155]. Even in some refractory SS patients, anti-PD-1 in combination with HDAC
inhibitors can promote durable clinical response [156]. In a Phase1/2 trial of anti-PD-L1
(durvalumab) and lenalidomide in CTCL patients, Querfeld et al. showed that durvalumab
and lenalidomide are associated with significant clinical activity in refractory and advanced
patients [157].
Given the role of cytokines and chemokines in CTCL pathogenesis, studies exploring
their therapeutic potential on the CTCL TME have also emerged [151,158]. EQ101 (formerly
Cancers 2024, 16, 3368 10 of 18

known as BNZ-1) is a synthetic peptide, designed to selectively inhibit IL-2, IL-9, and IL-15
binding to the common gamma chain (γc) signaling receptor, leading to the depletion of
Tregs and tumor growth suppression [159]. Moreover, denileukin diftitox, a recombinant
fusion protein of IL2 and diphtheria toxin, targets the IL2 receptor on malignant T cells and
Tregs [20]. The reengineered drug denileukin difitox-cxdl (E7777) shows improved safety
and tolerability and was FDA-approved in August 2024 for relapsed/refractory CTCLs.
Mogamulizumab, which is a humanized anti-CCR4, exhibits potent clinical efficacy against
CCR4-positive CTCLs and other T cell lymphomas and was shown to efficiently decrease
Tregs, leading to CTCL growth inhibition [160]. KIR3DL2 expression is upregulated on all
subtypes of CTCLs. Anti-KIR3DL2 monoclonal antibody (IPH4102) has shown promise
in depleting the KIR3DL2 receptor in malignant T cells of CTCL patients [161]. IPH4102
has been shown to recruit human effector NK cells as well as macrophages to eliminate
KIR3DL2+ T cells via antibody-dependent cell cytotoxicity and antibody-dependent cell
phagocytosis, respectively. Wang et al. compared the efficacy of CCR4-IL2 bispecific
immunotoxin with brentuximab. Using an immunodeficient NSG mouse model of CTCLs,
the study found that CCR4-IL2 bispecific immunotoxin was more effective in prolonging
survival than brentuximab [158].

5. Conclusions
Malignant T cells can turn their environment into a hospitable home to promote their
survival, growth, and progression. Hence, in our quest to uncover the therapeutic potential
of CTCL TME, agents or drugs should not only target malignant T cells but interfere
with their key defensive mechanisms and abrogate their ability to evade the antitumor
immune response. To this end, the reprogramming of protumorigenic immune cells to
gain their antitumor functions and apoptosis induction of CTLC cells holds promise in
CTCL treatment. Such a holistic approach will open new opportunities in the treatment of
relapsing and refractory CTCL patients to yield durable clinical responses.

Author Contributions: Conceptualization, L.B.K. and C.Q.; writing—original draft preparation,

L.B.K.; writing—review and editing, S.T.R. and C.Q. All authors have read and agreed to the published
version of the manuscript.
Funding: This research was supported in part through the National Institutes of Health (NIH)/National
Cancer Institute (NCI) Cancer Center Support Grant (P30CA 033572) to the City of Hope, NIH/NCI
grant (R01 CA229510-01) and The Leukemia and Lymphoma Society Clinical Scholar Award to
C. Querfeld, used in the capacity of mentoring coauthor.
Acknowledgments: C. Querfeld is a Scholar in Clinical Research of The Leukemia and Lymphoma Society.
Conflicts of Interest: L.B.K: None to declare. S.T.R: Is a consultant with Pepromene Bio, Inc; Abbvie;
is a member of the Educational Advisory Board of Pepromene Bio, Inc; and has stock options with
Pepromene Bio, Inc. C.Q.: Consultant to Helsinn, Kyowa Kirin, and Citius Pharmaceuticals Inc;
contracted clinical investigator to Kyowa Kirin, Sirpant immunotherapeutics, Bristol Myers Squibb,
and BioInvent; received research grants from Helsinn and Kyowa Kirin.

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