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About the Editors
Shyamasree Ghosh, MSc, PhD, PGDHE, PGDBI, has been
working in the capacity of Scientic Ofcer G at the School
of Biological Sciences (SBS), National Institute of Science
Education and Research (NISER), Bhubaneswar, Orissa,
India, since 2009, an OCC of HBNI, Mumbai. She gradu-
ated from the prestigious Presidency College Kolkata, under
Calcutta University, in 1998, with honors in zoology, and
with chemistry and physiology as additional subjects, and
was awarded the prestigious National Scholarship from the
Government of India in the same year. She completed her postgraduate studies in
biotechnology at Calcutta University, ranking second in the university in 2000.
She completed her PhD from the Indian Institute of Chemical Biology (IICB),
CSIR, Kolkata, after qualifying for the National Eligibility Test conducted by the
Ministry of HRD, Government of India. Her PhD work in 2005 in the eld of child-
hood acute lymphoblastic leukemia (ALL) was published in various national and
international journals of repute. Later, she worked in the eld of stem cells and nan-
otechnology during her postdoctoral research as a Stem Cell Scientist at Manipal
Health Systems, Bangalore, and the Indian Association for the Cultivation of
Sciences (IACS), Kolkata. She served as the Head of the Biotechnology Department
in a postgraduate college afliated with Bangalore University until 2009.
She has authored and edited 16 books, both as a single author and jointly with
other co-authors. Her publications have been widely cited globally, and she has received
several awards in India for her academic endeavors.
Sanjima Pal, MSc, PhD, is currently working as a Research
Associate (Staff Scientist) at the Research Institute of the
McGill University Health Centre (RI-MUHC) in Canada. She
leads a project focused on developing a patient-specic, tumor-
microenvironment-inclusive organ-on-chip platform to predict
individualized chemosensitivity. Additionally, she is investi-
gating altered lipid metabolism as a driver of chemoresistance
and a potential therapeutic target in gastroesophageal cancer.
She earned her doctoral degree in immune-chemical biology in 2017 from the
School of Biological Sciences (SBS) at the National Institute of Science Education
and Research (NISER), Bhubaneswar, Odisha, India. From 2016 to 2017, she worked
as a Research Associate at the Crystallography and Molecular Biology Division of
the Saha Institute of Nuclear Physics, Kolkata.
She completed a postdoctoral research training in the Department of Radiation
Oncology at the University of Michigan, Ann Arbor (2017–2020), where she con-
tributed to a drug discovery project focused on developing a novel class of small
molecules designed to degrade EGFR by disrupting its dimerization. During her
second postdoctoral fellowship at McGill University, she established a microuidic
xi
xii About the Editors
organ-on-chip platform capable of simulating clinical conditions for modeling
esophageal adenocarcinoma.
She is currently a member of a clinical trial team, contributing to the analysis
of immune landscapes in patients with gastroesophageal adenocarcinoma undergo-
ing perioperative chemo-immunotherapy. Her work has been widely cited, and she
has presented her research at numerous national and international conferences. She has
received several awards and fellowships in recognition of her academic achievements.
xiii
Contributors
Waliza Ansar
Assistant Professor Behala College
Kolkata, India
Debasis Bisoi
Assistant Professor, Department of
Pharmacology
All India Institute of Medical Sciences
(AIIMS)
Bibinagar, Telangana, India
Suchandra Chowdhury
Postgraduate Department of Zoology
Bethune College
Kolkata, India
Lopamudra Das
Assistant Professor, Department of
Botany, JKBK Government College
Cuttack, India
Rathi Dasgupta
Chief Technology Ofcer,
XData Lab Visiting Fellow Loyola
University at Chicago
Chicago, USA
Mirudula Elanchezhian
Department of Biology
University of Oxford
Oxford, United Kingdom
Shyamasree Ghosh
School of Biological Sciences
National Institute of Science
Education, and Research (NISER),
Bhubaneswar, India
Ashwin Kumar Jainarayan
Department of Neurology and
Neurological Sciences
Stanford University, Stanford, USA,
and Kennedy Institute of
Rheumatology Nufeld
Department of Orthopaedics
Rheumatology, and Musculoskeletal
Sciences
University of Oxford, United Kingdom
Ananya Jana
Department of Surgery
McGill University
Montreal, Canada
Sanjima Pal
Cancer Research Program Research
Institute–McGill University Health
Centre
Montreal, Canada
Arpit Kumar Pradhan
Department of Psychology
University of Michigan
Ann Arbor, USA
Cameliya Singha Roy
Department of Surgery
McGill University
Montreal, Canada
1
1
Tumor Microenvironment
An Overview Since Its
Conceptualization
Shyamasree Ghosh and Suchandra Chowdhury
1.1 TUMOR MICROENVIRONMENT (TME)
The tumor microenvironment (TME) refers to the environment in which tumors or
cancer cells exist. The evolution of cancer, in orchestration with distinct alterations
in the surrounding stroma, represents one of the most pivotal processes in oncol-
ogy. The cancer cells and surrounding stromal cells secrete cytokines, chemokines,
metabolites, and other factors and functionally mold their microenvironment for sur-
vival (Hinshaw et al., 2019). The milieu comprises noncancerous cells and other
associated components found in the tumor, including the biomolecules produced,
released, and consumed by them. The incessant interactions between tumor cells and
the TME play pivotal roles in tumor initiation, progression, metastasis, and response
to therapy. The TME is a fantastic therapeutic target in cancer treatment (Xiao
et al., 2021; Witz, 2009; Arneth, 2019). The chief cellular components of the TME
are stromal cells, like broblasts, endothelial cells, neurons, adipocytes, and immune
cells. In contrast, the noncellular components are the extracellular matrix (ECM)
and soluble biomolecules such as chemokines, cytokines, growth factors, circulat-
ing nucleic acids (DNAs, RNAs), and extracellular vesicles (EVs) (Xiao et al., 2021;
Stejskal et al., 2023, Figure1.1). The interactions, facilitated either through direct
cell-to-cell communication or indirectly via signaling molecules, such as cytokines,
chemokines, and growth factors, are essential for tumor progression, immune eva-
sion, angiogenesis, and metastasis.
1.2 TME: AJOURNEY THROUGH HISTORY
The concept of the TME was proposed by Rudolf Virchow in 1863 while establishing
the relationship between inammation and cancer. Rudolph Virchow’s hypothesis
that inammation promotes carcinogenesis and tumor progression has emerged as an
essential facet of the TME area (Schmidt et al., 2006). It was veried that inamma-
tory cells (mainly macrophages) and pro-inammatory molecules like cytokines and
chemokines, whose purpose is to protect against infectious agents, are involved in
the initiation of some cancer (inammation-linked cancers) or tumor progression of
essentially all types of cancer. Many studies showed the inltration of mononuclear
DOI: 10.1201/9781003405023-1
2 The Dynamics of Tumor Microenvironment and Therapeutic Targets
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3Tumor Microenvironment
cells in solid tumors and their involvement in the pro-malignancy functions of can-
cer-associated inammation (Witz, 2009; Jin et al., 2020). Stephen Paget was the
pioneer in proposing the role of the TME in tumor progression in 1989. He formu-
lated the “seed and soil” theory, thus laying the foundations of TME research. This
concept went unrecognized for many years. In the 20th century, a few people revis-
ited his ideas (Witz, 2009). In 2011, Hanahan and Weinberg recognized the emerging
participation of the TME in cancer development (Jin et al., 2020). Earlier studies on
the immune microenvironment of cancer remained conned to the characterization
and functions of cellular and humoral immune components in the TME (Witz, 2009;
Maman et al., 2018).
1.3 TME COMPONENTS
The components of the TME can be grouped into cellular and acellular elements.
Cellular components include noncancerous cells like broblasts, endothelial cells,
neurons, adipocytes, and immune cells (Hinshaw et al., 2019; Witz, 2009; Arneth,
2019). Atumor-nerve-immunity cycle in the TME negotiates communication among
cancer cells, immune microenvironment, and innervated niche, thus revealing a rela-
tionship among stress, immunity, and cancer (Iñigo-Marco et al., 2019, Figure1.2).
FIGURE 1.2 The network of intercellular interactions in the tumor microenvironment:
Diagram illustrating intercellular interactions within the tumor microenvironment. Key com-
ponents include tumor cells, cancer-associated broblasts (CAFs), immune cells, endothelial
cells, and extracellular matrix (ECM). Bidirectional crosstalk among cells emphasized the
dynamic and reciprocal nature of these interactions.
4 The Dynamics of Tumor Microenvironment and Therapeutic Targets
1.3.1 Cells
1.3.1.1 Immune Cells
The existence and role of lymphocytes in the TME were rst reported in 1976 by
Eva Klein and colleagues (Klein et al., 1976). Awide range of immunocytes is a
crucial constituent of tumor stroma. Both innate immune cells (macrophages, neu-
trophils, dendritic cells, innate lymphoid cells, myeloid-derived suppressor cells,
and NK cells), as well as adaptive immune cells (T cells and B cells), contribute
to tumor progression when present in the TME (Hinshaw et al., 2019; Witz, 2009;
Arneth, 2019).
1.3.1.1.1 T Cells
The signicant players in adaptive immunity are effector T cells. (Crespo et al.,
2013). Tumor-inltrating T lymphocytes exhibit antitumor cytotoxicity as well as
immune-suppressive activities. The cytotoxic activity of tumor-inltrating lympho-
cytes (TILs) is lower than that of lymphocytes from distant sites (Vose et al., 1977;
Maman et al., 2018).
Some T cells promote tumorigenesis, while others are tumor restrictive. The CD8+
memory T cells, a common type of T lymphocytes in the TME, are cytotoxic and
capable of contributing to excellent cancer prognoses by killing tumor cells (Hivroz
et al., 2012). The CD4+ T helper 1 (TH1) cells release interferon-gamma (IFN-γ) and
interleukin-2 (IL-2), helping the CD8+ T cells in the TME (Wang et al., 2004). TH17
cells produce interleukins like IL-17A, IL-17F, IL-21, and IL-22 to promote tumor
growth by favoring antimicrobial tissue inammation (Arneth, 2019).
Regulatory T cells (Tregs) often facilitate the development of an immunosup-
pressive TME to promote cancer by suppressing the antitumor immune responses.
Accumulation of FoxP3+ Tregs within the TME indicates poor prognosis of cancer
patients. Depletion of Tregs can induce the regression of metastatic lesions in patients
with advanced-stage melanoma. Additionally, the depletion of Tregs and subsequent
cancer antigen vaccination instigates antitumor CD4+ T cell responses. (Hsieh et al.,
2012; Arneth 2019).
A poor co-stimulatory, high co-inhibitory T cell anergy-promoting environment
often promotes cancer progression. Evidence indicating antigen-specic T cell-
intrinsic dysfunction in the tumor microenvironment is apparent. Thus, T cell anergy
can be one of the immune evasion mechanisms in patients with Cancer (Broderick
et al., 2006; Crespo et al., 2013).
The phenomenon of resistance of effector T cells to reactivation with decreased
cytokine expression and effector function is known as T cell exhaustion. It occurs
when T cells are frequently activated at sites of chronic inammation, like cancer.
The TME provides the required circumstances for effector T cells to become func-
tionally exhausted and maintain this state during disease progression. However, the
detailed molecular signals remain vague (Wherry, 2011; Crespo et al., 2013).
Senescent T cells are characterized by shortening telomere, loss of CD28 expres-
sion, and cell cycle arrest. These cells demonstrate defective killing abilities and the
development of adverse regulatory functions. Tumor cells can induce T cell senes-
cence to promote tumorigenesis in the TME (Montes et al., 2008). Thus, peripheral
5Tumor Microenvironment
T cell tolerance mechanisms, like regulatory T cells, T cell anergy, exhaustion,
and senescence, impair ongoing T cell immunity and enable tumor immune escape
(Crespo et al., 2013).
1.3.1.1.2 B Cells
Until the 1970s, the tumor-enhancing immunoglobulins (Ig) source in the TME
passively supported the presence of tumor-inltrating B lymphocytes (Witz,
1977). The underlying mechanisms of the pro-malignancy function of Ig and
cytokine-secreting tumor-inltrating B cells were re-examined in the 2000s (Tan
et al., 2007). In the TME, B cells are found at the invasive margin of tumors,
more commonly in draining lymph nodes and lymphoid structures adjacent to the
TME. B cell inltration into the TME is associated with good prognosis in some
breast and ovarian cancers (Coronella et al., 2001); however, in mouse models,
the presence of B cells inhibits tumor-specic cytotoxic T cell responses (Qin
etal., 1998).
B cells promote tumor development by activating Fcγ receptors (FcγRs) on
myeloid cells. Operational analyses revealed that tumor-associated Igs increase tumor
growth (Ran et al., 1972). The tumor-associated Igs are afxed to tumor cells by
epitope–antibody interaction or by binding to FcγRs expressed by epithelial or mes-
enchymal tumors (Ran et al., 1976; Braslawsky et al., 1976). The FcγRs transduce
pro-malignancy signals to tumor cells upon binding the corresponding immunoglob-
ulin ligand (Zusman et al., 1996). In contrast, FcγRs expressed by immunocytes play
crucial roles in antitumor immune reactivities (Maman et al., 2018).
An immunosuppressive population of IL-10-producing B cells, termed B10 cells
or regulatory B cells (Bregs) (Mauri et al., 2012), increases tumor burden and inhib-
its tumor-specic immune responses in inammation-induced skin cancer (Schioppa
et al., 2011). The B lymphocytes, including the regulatory B cells, regulate tumor cell
survival, propagation, and progress of treatment resistance. Additionally, these cells
have been linked to fostering immune escape (Balkwill et al., 2012).
1.3.1.1.3 NK Cells
The innate cytotoxic lymphocytes, namely, the natural killer (NK) cells and natu-
ral killer T (NKT) cells, also inltrate the tumor stroma but are not found in
proximity with the tumor cells. They induce antitumor cytotoxicity (Vose et al.,
1977) and provide antitumor resistance mechanisms (Vivier et al., 2011; Maman
et al., 2018).
NK and NKT cells express and use inhibitory, adhesion, activating, and cyto-
kine receptors to identify cellular targets and spare healthy cells. The signals from
these receptors can be transduced simultaneously during contact with cells in the
TME to dictate the activation of NK cells (Vivier et al., 2011). NK and NKT cells
identify internal changes in host tissues through “stress-induced” self-recognition
and activate adaptive and innate immune cells in the TME (Birbrair et al., 2014;
Arneth, 2019). They are good prognostic markers in cancers like colorectal, gas-
tric, lung, renal, and liver. Studies report that NK cells in the tumor stroma have an
anergic phenotype that is induced by malignant cell-derived transforming growth
factor beta (TGF-β) (Fridman et al., 2012; Balkwill et al., 2012).