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Unraveling the Esophageal Cancer Tumor
https://t.me/med1917
Microenvironment: Insights and Novel
Immunotherapeutic Strategies
Inamu Rashid Khan, Faizyana Ali, Sheema Hashem,
Alanoud Abdulla, Sabah Nisar, Tariq Masoodi,
Ammira S. Al-Shabeeb Akil, Ajaz A. Bhat, and Muzafar A. Macha
Abstract
Esophageal cancer remains one of the most challenging cancers to treat, with a
poor prognosis due to factors such as late detection, high mortality rate, and
aggressive nature. This makes it a significant global health concern. The devel-
opment of esophageal squamous cell carci noma has been linked to genes like p53
and Rb, which regulate the cell cycle. Harmful mutations in these genes lead to
uncontrolled cell division and cancer progression. The tumor microenvironment
Authors Inamu Rashid Khan and Faizyana Ali have contributed equally to this work.
I. R. Khan
Department of Zoology, School of Life Sciences, Central University of Kashmir, Ganderbal,
Jammu & Kashmir, India
F. Ali
Department of Clinical Biochemistry, University of Kashmir, Hazratbal Srinagar,
Jammu and Kashmir, India
S. Hashem
Department of Human Genetics, Sidra Medicine, Doha, Qatar
A. Abdulla · A. S. Al-Shabeeb Akil · A. A. Bhat (
Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program,
Sidra Medicine, Doha, Qatar
e-mail: abhat@sidra.org
S. Nisar
St. Jude Children’s Research Hospital, Memphis, TN, USA
T. Masoodi
Human Immunology Department, Research Branch, Sidra Medicine, Doha, Qatar
M. A. Macha (
Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology,
Kashmir, India
e-mail: muzafar.macha@iust.ac.in
✉)
✉)
#
The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
Interdisciplinary Cancer Research, https://doi.org/10.1007/16833_2023_172
Published online: 2 August 2023
215
216 I. R. Khan et al.
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of esophageal cancer contains various innate immune cells, including natural
killer cells, tumor-associated macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, and mast cells. These cells, along with other diverse
cell populations within the tumor microenvironment, inhibit cell death, and
promote blood vessel formation, invasion, and metastasis. Immunological
checkpoints, secreted chemicals, and immune cells with negative effects all
contribute to the ability of esophageal cancer cells to resist the immune system
and suppress antitumor immunity. Understanding how the tumor microenvironment evolves in different esophageal cancer subtypes and recognizing the
similarities and differences among tumor microenvironments in various cancer
types are critical for developing targeted therapies in the future. Cancer immunotherapy represents a potentially new treatment approach for esophageal cancer.
Recently, checkpoint inhibitors such as programmed cell death protein
1, programmed death-ligand 1, and cytotoxic T-lymphocyte-associated protein
4 have been proposed as strategies to enhance tumor cell destruction and restore
T-cell activity in esophageal cancer specifically. To improve the effectiveness of
immunotherapy and develop innovative methods for prognos tic prediction or
treatment, comprehensive knowledge of the immunological landscapes within
esophageal cancer is essential.
Keywords
Angiogenesis · Checkpoint inhibitors · Esophageal cancer · Immunotherapy ·
Innate immune cells · Prognostic prediction · Tumor microenvironment
Abbreviations
APC Antigen-presenting cells
BE Barret’ s esophagus
CAFs Cancer-associated fibroblasts
CRT Radiation therapy
CTLA-4 Cytotoxic T-lymphocyte-associated protein 4
DCs Dendritic cells
EAC Esophageal adenocarcinoma
EC Esophageal cancer
ESCC Esophageal squamous cell carcinoma
GERD Gastroesophageal reflux disease
HGF Hepatocyte growth factor
MCs Mast cells
MDSCs Myeloid-derived suppressor cells
NK cells Natural killer cells
ORR Objective response rates
PD-1 As programmed cell death protein 1
PD-L1 Programmed death-ligand 1
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TAMs Tumor-associated macrophages
TAPs Tumor-associated platelets
Th17 cells T helper 17 cells
TIM-3 T-cell immunoglobulin and mucin domain-3
TLRs Toll-like receptors
TME Tumor microenvironment
1 Introduction
Esophageal cancer (EC) is the most lethal and aggressive among all gastrointestinal
(GI) malignancies. With an annual incidence of 572,000 and 47,000 and 509,000
and 42,000 deaths, EC is the sixth and fourth most common cause of cancer-related
deaths worldwide and in India, respectively (Bray et al. 2018; Siegel et al. 2018).
Among many states of India, Kashmir has the third highest incidence of EC in the
world (Khuroo et al. 1992; Mir and Dar 2009; Wani et al. 2014). Despite significant
advances in surgery and chemotherapy (CT) (Carboplatin, Paclitaxel, 5FU, Cisplatin) or targeted therapy (TT) (anti-EGFR) based chemo-radiation therapy (CRT),
EC is still characterized by poor prognosis and low survival rates (5-year survival
is 15–20%) (Pennathur et al. 2013), primarily due to an advanced stage of cancer at
the time of detection, loco-regional/distant metastasis and failure to the currently
available CRT’s. This poor response includes inherited and acquired resi stance to
the CRT/TT treatment and associated severe toxicities resulting in significant
co-morbidities (Rivelli et al. 2015). Differential response levels to chemotherapeutic
drugs and other treatment regimens further exacerbate the problem. A complete
understanding of the underlying pathology of EC might help us overcome the
inadequate therapeutic response and help identify novel therapeutic strategies with
minimal inherent or acquired resistance. Moreover, identifying prognostic and
diagnostic biomarkers is necessary, including a panel of serum, surface, and genetic
markers which can help both to identify the type and stage of cancer and provide a
way to generate immune detection in immunotherapeutic systems (Huang and Fu
2019). Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarci-
noma (EAC) are the two primary forms of EC, which vary in their origin and clinical
characteristics. While the ESCC develops from the stratified squamous epithelial
lining of the organ, EAC develops from the columnar glandular cells of the epithelium. ESCC is one of the most aggressive types of cancer, frequently showing lymph
node metastasis and tumor invasion into adjacent organs, even in the early stages.
With respect to location, the incidence rate of EC varies greatly. The incidence of
EAC is increasing in Western countries. However, ESCC remains the significant
type of cancer in many Asian countries, including India (80%) (Zhang et al. 2012).
The major risk factors for the development of both ESCC and EAC includes the
consumption of smoking, tobacco chewing (Brooks et al. 2009), alcohol
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consumption, diet low in zinc (Choi et al. 2018), achalasia for ESCC (Lambert and
Hainaut 2007) or obesity, chroni c gastroesophageal reflux disease (GERD ) (Zhang
et al. 2012; Mansour et al. 2017). In addition, epigenetic factors, inherent genetic
predisposition, unique dietary habits, and obesity are the potential causes of
EC. Barret’s esophagus (BE), a premalignant condition in which columnar intestinal
cells take the place of the lower esophagus’s usual squamous epithelial lining
(Spechler 2013; Sh arma 2022), is regarded as a severe chronic GERD with longterm consequences (Jankowski et al. 1999). According to estimates, 2% of the
general population is at risk for BE [14], whereas 10% of GERD patients are at
risk of developing EC (Spechler 2013). While the incidence of BE is increasing
among many countries, including the USA, approximately 0.12–0.5% of people
with BE are estimated to develop EAC annually.
Genes that oversee and regulate cell cycle proteins like p53 and Rb play a
significant role in the emergence of EC (Niyaz et al. 2020; Zhu et al. 2020).
Deleterious mutations render these genes ineffective and allow uncontrolled cell
division and cancer development (Engeland 2022). Additionally, 76% of ESCC
patients have elevated levels of the epidermal growth factor receptor (EGFR), which
is usually accompanied by a dismal prognosis. In addition, 78.6% of ESCC patients
have alterations or amplifications in pathways for a receptor tyrosine kinase (RAS)
and protein kinase B (AKT) that are downstream of the EGFR (Huang and Yu 2018)
(Fig. 1).
2 Immune System
The immune system comprises two prim ary parts, including the innate and adaptive
immune systems. The innate immune system, which already exists in the body,
serves as the initial line of protection and is activated when an antigen enters the
body. The adaptive immune system is typically silent but combats microorganisms
that escape or outperform innate immunity (Cianci et al. 2019). The innate immune
system is made up of immune cells, including pathogen-clearing cells such as
T cells, B cells, natural killer cells (NK cells), Langerhans cells, dendritic cells
(DC), macrophages, platelets, mast cells (MCs), complement systems and cytokines
that are quickly committed to an infection site during the inflammation. Antigenpresenting cells (APC) stimulate the adaptive immune system, including B and
T cells with a large complex of antigen receptors, including toll-like receptors
(TLRs) and major class II histocompatibility complex (MHC II) molecules involved
in identifying pathog ens and presenting antigens respectively. Antigens mounted on
the APC cells bind specifically with the receptors on the B and T lymphocyte and
promote their proliferation, maturation, and activation (Gaudino and Kumar 2019).
Immunotherapies are the treatment of choice for both early and advanced cancers,
including EC. While some tumor cells express immunological checkpoint proteins
such as programmed death ligand-1 (PD-L1), lymphocytes express their ligands like
programmed cell death protein 1 (PD-1) that prevent the destruction of the tumor
cells by lymphocytes (Kelly 2019). Similarly, a transmembrane receptor cytotoxic
Unraveling the Esophageal Cancer Tumor Microenvironment: Insights... 219
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Fig. 1 Schematic diagram of the EGFR signaling pathway. EGFR activation occurs when a ligand
such as EGF binds to EGFR and causes receptor dimerization. The receptor dimerization leads to
the auto-phosphorylation of growth factor proteins such as GRB2 and PLCγ, tyrosine kinase JAK,
and proto-oncogene Src and adaptor protein SHC, which results in the activation of downstream cell
survival pathways such as RAS-RAF-MEK-ERK, JAK/STAT, PI3K/mTOR and NF-kB pathways
Abbreviations: EGFR: epidermal growth factor receptor; PLCγ: phospholipase C gamma;
JAK: Janus kinase; Src: Src homology 2 domain-containing
T lymphocyte-associated protein 4 (CTLA-4) on T cells suppress their activation by
its ligands (CD80 or CD86) present on the tumor cells (Bhat et al. 2021a, b).
Checkpoint inhibitor therapy, a kind of cancer immunotherapy, targets important
immune system regulators that cancer cells employ to defend themselves from
immune attack. Recently, intriguing alternatives for the targeted treatment have
been proposed, including checkpoint inhibitors that target PD-1, PD-L1, or
CTLA4 (Fig. 2) (Wang et al. 2022).
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Fig. 2 Immune checkpoint therapy in EC. T-cells recognize tumor-specific antigens present on the
surface of antigen-presenting cells or tumor cells through the TCR. The binding of PD-1 checkpoint
protein present on the T cells with the ligand PD-L1 on the tumor cells inactivates the T-cell
function resulting in the inhibition of tumor cell killing. CTLA-4 is a receptor on T cells that binds
to CD80/86 on antigen-presenting cells and downregulates the immune system. Monoclonal
antibodies such as -anti-PD-L1 drugs (Pembrolizumab and Nivolumab) and anti-CTLA4 drugs
(Tremelimumab and Ipilimumab) that function as immune checkpoint inhibitors can be used to
restore the immune response against EC
Abbreviations: EC esophageal cancer, TCR T-cell receptor, PD-1 programmed-cell death protein
1, PD-L1 programmed-death ligand 1, CTLA4 cytotoxic T lymphocyte-associated protein 4, MHC
major histocompatibility complex
3 Immune System-Mediated Esophageal Cancer Initiation
Progression
For decades, identifying and characterizing epigenetic alterations in tumor cells was
the main focus of cancer initiation and development. However, these research
findings did not translate well from bench to bedside. Recent studies have conclusively established the importance of tumor mic roenvironment (TME), particularly
the presence of immune cells in the initiation and progression of cancers, including
EC (Diao 2020). Immune cells, including NK cells, tumor-associated macrophages
(TAMs), regulatory T cells (T-regs), DCs, MCs, myeloid-derived suppressor cells
(MDSCs), neutrophils, tumor associated-platelets (TAPs) and associated cytokines
and chemokines are present in the EC TME (Cui et al. 2021). Along with these
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immune cells, a variety of other stromal cells including cancer-associated fibroblasts
(CAFs), neuroendocrine cells, endothelial cells, adipocytes, blood lymphatic vascular cells, and pericytes contribute to immune escape, increasing angiogenesis,
invasion & metastasis, therapeutic resistance and therefore promote aggressive
tumor behavior (Bhat et al. 2021a, b; Cui et al. 2021). During the early stages of
tumor formation, the presence of neo-antigens and tumor-associated antigens trigger
DC-mediated activation of cytotoxic T lymphocytes, immunological checkpoints,
and tumor cell-released substances negatively regulate immune cells and decrease
antitumor immunity. The following are distinct cell types and risk factors linked to
the development of EC.
3.1 Myeloid-Derived Suppressor Cells
MDSCs are immune cells in the TME that negatively modulate immunological
reactions during inflammation and cancer. Monocytic MDSCs (M-MDSCs) and
polymorphonuclear MDSCs (PMN-MDSCs) are the two primary subpopulations
of MDSCs. The growth of MDSCs in the TME is induced by tumor-derived
substances such as granulocyte-macrophage colony-stimulating factor (GM-CSF)
and granulocyte colony-stimulating factor (G-CSF) (reviewed in Bhat et al.
2021a, b). Inflammation, specifically pro-inflammatory chemicals like IL-1, IL-6,
and prostaglandin E2, as well as other tumor-secreted substances, including vascular
endothelial growth factor (VEGF) stimulate and increase MDSCs. Many studies
have shown that cancer patients with higher MDSCs have a worse prognosis than
those with low numbers. Furthermore, elevated MDSC levels have been found in EC
patients and are linked to advanced disease. These MDSCs suppress antitumor
immunity by several mechanisms, including direct inhibition of NK cell cytotoxicity, inhibition of T-cell activation, promoting tumor cell growth, invasion & metastasis, and therapeutic resistance (reviewed in Bhat et al. 2021a, b). In addition, by
activating T-regs, MDSCs promote immunological suppression and impair T cellmediated tumor clearance (reviewed in Bhat et al. 2021a, b). The majority of the
enzymatic activity necessary for MDSCs to inhibit T-cell proliferation and activation
is provided by arginase-1 and inducible nitric oxide synthase-2 (iNOS). While
arginine is converted into urea and L-ornithine, arginase-1 depletes arginine from
T cells, lowering the expression of the CD3ζ chain and impairing T cells’ ability to
respond to activating signals (Rodriguez et al. 2003). Recent research has
demonstrated that M-MDSCs produced by extracellular vesicles generated from
melanoma might predict immunotherapy resistance (Zhao et al. 2021). Similarly,
M-MDSCs and PMN-MDSCs also showcase various strategies for controlling the
development of tumors. Even though PMN-MDSCs are more common in tumors,
M-MDSCs exhibit more potent suppressive properties (Marvel and Gabrilovich
2015).
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3.2 Regulatory T Cells
Regulatory T cells (Tregs) are a very small subpopulation of T cells that suppress the
exaggerated immunological response to maintain homeostasis and self-tolerance
(Kondĕlková et al. 2010). In healthy physiology, Tregs are also known to regulate
+
CD4
and CD8+T cells, macrophages, B cells, NK cells, and DCs. However, they
also suppress antitumor immune response as well. Tregs play a major role during
tumorigenesis by suppressing inflammation and attenuating antitum or immunity by
releasing immunosuppressive cytokines, interfering with the presentation of tumorassociated anti gens, cytotoxic cell activity, and granule release inhibition (Vignali
et al. 2008; Lab ani-Motlagh et al. 2020). However, the depletion of Tregs promotes
tumor antigen-specific immunity and rejection of endogenous immune-mediated
malignancies, highlighting the importance of Treg cells for antitumor immunity
(Fietta et al. 2009). Therefore, modulation of Tregs represents a novel cancer
therapeutic opportunity. CCL17 and CCL22 produced by tumor cells &
macrophages activate C-C chemokine receptor 4 (CCR4) and attract Tregs recruitment to the EC microenvironment. While the Treg infiltration is associated with
deeper tumor invasion, metastasis, overall disease severity, and shorter postchemotherapy survival, immunotherapy and CTLA4 inhibition were more effective
in Treg-depleted patients than non-depleted patients (Fietta et al. 2009). Among the
many suppression functions of Tregs, those essential for preserving self-tolerance
(i.e., the systems whose deficiency results in autoimmune illness) greatly affect
tumor immunity. Surprisingly, the Foxp3 transcription factor regulates a few downstream molecules, including IL-2 receptor subunits (CD122, CD25) and CTLA-4,
and their absence abolishes Treg-suppressive action but promotes autoimmune
disorders (Sakaguchi et al. 2008). In addition, Foxp3 interacts with transcription
factors (NFAT and AML1) and inhibits IL-2 synthesis (Ono et al. 2007), thereby
making Tregs dependent on activated conventional T cells (Tconv) for IL-2 (Fig. 3).
3.3 T Helper 17 Cells
T helper 17 (Th17) cells, a small subpopulation of pro-inflammatory T-helper
cells, are known to regulate immunomodulation with both anti-cancer and
pro-tumorigenic properties. Upon stimulation by transforming growth factor-β
(TGF-β) and IL-6, Th17 cells limit the proliferation of CD8
ectonucleotidases CD39 and CD73 (Zhang 2018). Through the secretion of
cytokines, including IL-17 and IL-22 via STAT3 pathway activation, these Th17
cells promote angiogenesis and accelerate cancer growth (Tesmer et al. 2008). Based
on the composition of TNF-, IL-1, IL-6, IL-21, TGF, and IL-23 in the TME (Nam
et al. 2008), Th17 cells have been shown to transform into either Tregs or Th1 cells
performing a range of contrasting tasks. While both the Tregs and Th17 (CD4+
T cell subtypes) actively contribute to the growth and spread of lung cancers
(Marshall et al. 2016), Th17 cells, in part, function as an independent predictor for
EC lymph node metastasis and poo r patient prognosis (Chen et al. 2012). In addition
+
T cells by expressing
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Fig. 3 Cancer evasion of immune surveillance via TME-mediated cytokines/chemokines. Several
chemokines and cytokines secreted by cancer cells block the actions of NK cells, DCs and T cells
and attract TAMs. Additionally, MDSCs and Treg T cells are produced by tumour cells, which can
further limit T cell activity. PD-L1/2 is expressed by TAMs and tumour cells to prevent T-cell
activation by the PD-1 receptor. Collectively, these cells promote tumour development and proliferation while suppressing antitumor immunity by various mechanisms
to TME, increased Th17 cells have been reported in the peripheral blood of both
EAC and ESCC patients and are associated with the tumor stage (Huang and Fu
2019).
3.4 Tumor-Associated Macrophages
Macrophages involved in innate and adaptive immune responses are crucial cells for
tissue homeostasis and protect the body against invading pathogens. Based on the
presence of interferons in the microenvironment, macrophages are polarized to either
pro-inflammatory M1 or anti-inflamm atory M2 phenotype. M1 macrophages by
secreting chemokines/cytokines (IL-12, IL-23, TNF-/CCL-5, CXCL9, CXCL10,
and CXCL5) activate Th1 cells and suppress cancer cell proliferation and inhibit
survival (Atri et al. 2018). M2 macrophages, on the other hand, release cytokines
including IL-1 receptor antagonist (IL-1ra), IL-10 & TGF-β and are crucial for tissue
remodeling, wound healing, angiogenesis, and the development of tumors
(Krzyszczyk et al. 2018). In addition, M2 macrophages closely resemble TAMs,
are extremely flexible, and adopt a variety of activation states between M1 and M2.
They are necessary for the breakdown of the extracellular matrix (ECM), remodeling
of the TME and motility of tumor cells, and the induction of angiogenesis. They
exhibit markers that are unique to both M1 (IFN-γ, TNFα, MMP-9, CCL2, CCL5,
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CXCL9, CXCL10, CXCL16, IL-12, & IL-23) and M2 (IL-10, TGF-β, arginase-1,
PPARγ) (Lin et al. 2019). Specifically to ECs, increased expression of tumor-derived
macrophage chemo-attractant protein-1 (MCP1) has been associated with generating
angiogenic enzymes such as thymidine phosphorylase, dismal prognosis, and ineffective treatment in ESCC patients (Shimada et al. 2002).
3.5 Cancer-Associated Fibroblasts
CAFs, characterized by the overexpression of fibrobl ast activation protein-α (FAPα)
and α-smooth muscle actin (αSMA), is a subpopulation of fibroblasts that is prevalent in the TME of many solid tumors, including ECs. These CAFs are a diverse
population of cells that are believed to be originated either from cancer cells,
reprogrammed tissue-resident fibroblast, fibrocytes, mesenchymal stem cells from
the bone marrow, epithelial & endothelial cells via epithelial to mesenchymal
transition (EMT) (Xing et al. 2010). This phenotype is hypothesized to be produced
by cancer-cell-secreted factors such as TGF. In addition, microRNAs secreted by the
cancer cells have been shown to transform fibroblasts into CAFs (Savardashtaki
et al. 2019). Many malignancies, including EC, are caused by chronic inflammation
and injury called non-healing wounds. Fibroblasts and other cells that typically
respond to injury are crucial to the development, progression, and eventual dissemination of malignancies via interaction with tumor and other stromal cells through
secreted factors that activate pro-inflammatory pathways, impairing immune surveillance and altering the ECM (Lin et al. 2016). Using a 3D organotypic cell culture
model, it has been shown that the hepatocyte growth factor (HGF) produced by
activated fibroblasts facilitates invasion by EC cells and promotes resistance to
cisplatin and 5-fluorouracil (Sakaguchi et al. 2008). Using in vivo mouse models,
it has been demonstrated that the development of EC was associated with the
invasion of MDSCs and activated fibroblasts resulting in a strong desmoplastic
response in the tumor stroma (Bhat et al. 2021a, b). A similar increase in tumor
cell proliferation, angiogenesis, and motility of cancer cells was observed by CAFs
using in vitro models. Furthermore, irradiation induced p120-catenin and HGF
upregulated by fibroblasts co-cultured with ESCC cells, reflecting a phenotype that
is more intrusive (Baba et al. 2020).
4 Targeted Immunotherapy in EC
Immunotherapy is a biological therapy that enhances the body’s defense mechanisms
using substances made by the body or in the lab to enhance, target, or restore immune
system function. Immunotherapy is a therapeutic procedure that improves or restores
the ability of the immune system to detect and eradicate tumor cells by altering or
preventing co-stimulatory cues. Co-stimulatory signals such as PD-1, cytotoxic
T lymphocyte-associated antigen 4 (CTLA4), lymphocyte activation gene
3 (LAG-3) & T-cell immunoglobulin, and mucin domain-3 (TIM-3) fine-tunes the
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