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The Interplay Between Immunity and Gut Microbiota in Colon Cancer 245
https://t.me/med1917
to treatment, it has been detected an enrichment in Bifidobacterium strains. The
supplementation of these species restored the antitumoral efficacy of PD-1 blockade
in non-respondent mice lacking these bacteria (Sivan et al. 2015).
Moreover, augmented dendritic cell function and enhanced CD8-positive T-cell
priming and accumulation in the tumor microenvironment (TME) were shown to be
associated with the efficacy of PD-1 blockade as well as of anti-CL4.
4 Conclusion
The gut microbiota exists in a dynamic balance between symbiosis and pathogenesis
and can influence almost any aspect of host physiology. Even if a universal
CRC-associated microbiota is yet to be determined, great effort was put into
revealing the complexity of the mechanisms that unequivocally exist between
microbiota and tumors, and more should be done in this direction in the attempt to
deepen current knowledge and exploit the microbiota in all its potential, from its role
in the process of carcinogenesis to all possible preventive and therapeutic
applications.
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Immunotherapy in Gastrointestinal Cancer
https://t.me/med1917
Focusing on CAR-T Cell Therapy
Asma Mousavi, Faeze Gharibpoor, Sepideh Razi, and Nima Rezaei
Abstract
Cancer is a leading cause of death worldwide, accounting for nearly ten million
deaths in 2020. In this regard, gastrointestinal (GI) cancers are among the cancers
with the highest mortality rate. In the past, surgery, chemotherapy, radiotherapy,
and their combination were the only solutions for cancer treatment; however, the
emergence of immunotherapy has recently opened a new horizon in cancer
A. Mousavi
School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Cancer Immunology Project (CIP), Universal Scientific Education and Research Network
(USERN), Tehran, Iran
F. Gharibpoor
Cancer Immunology Project (CIP), Universal Scientific Education and Research Network
(USERN), Tehran, Iran
Student Research Committee, Faculty of Medicine, Guilan University of Medical Sciences, Rasht,
Iran
S. Razi
Cancer Immunology Project (CIP), Universal Scientific Education and Research Network
(USERN), Tehran, Iran
Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical
Sciences, Tehran, Iran
N. Rezaei (
Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical
Sciences, Tehran, Iran
Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran,
Iran
Cancer Immunology Project (CIP), Universal Scientific Education and Research Network
(USERN), Stockholm, Sweden
e-mail: rezaei_nima@tums.ac.ir
#
Interdisciplinary Cancer Research, https://doi.org/10.1007/16833_2023_152
Published online: 7 March 2023
✉)
The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
251
252 A. Mousavi et al.
https://t.me/med1917
treatment, especially hematological malignancies. Although there are various
methods of immunotherapy, the central concept behind all of them is using the
potential of host immune cells. To date, three types of tumor immunotherapies
have been used to treat GI cancers: immune checkpoint inhibitors (ICIs), vaccine
therapies, and adoptive cell therapy (ACT), which includes chimeric antigen
receptor (CAR)-T cells. CAR-T cell therapy is one of the most innovative and
attractive cellular immunotherapies rapidly evolving in the last decades. In this
method, the patient’s T cells are manipulated to express desired CARs to recog-
nize the tumor-associated antigens (TAAs). Some of the principal TAAs in GI
cancers are epithelial cell adhesion molecule (EpCAM), mucin 1 (MUC1), human
epidermal growth factor receptor 2 (HER2), and carcinoembryonic antigen
(CEA), which are covered in this review. Despite the remarkable progress in
the CAR-T cell method, several factors limit its clinical administration. The
current study aims to reveal the role of CAR-T cell therapy in GI cancers, its
limitations (cytokine release syndrome, neurotoxicity, disease relapse, and
on-target, off-tumor toxicities), as well as some practical strategies to improve
the safety of this method.
Keywords
CAR-T cell therapy · CTLA-4 · Gastrointestinal cancer · Immunotherapy · PD-1
1 Introduction
Worldwide, the prevalence of various types of cancer is rising, making them one of
the major causes of disability, morbidity, and mortality (Dahiya et al. 2021).
Gastrointestinal (GI) (including esophageal, stomach, liver and biliary system,
pancreas, and colorectal) cancers are among the most common type of malignancies
in terms of prevalence. In this way, colorectal cancers have the third-grade mortality
rate among all cancers (Siegel et al. 2021). The 5-year survival rate of GI cancers is
also low, especially in advanced stages (Yang et al. 2019). Early diagnosis by
expanding the treatment options can increase the survival rate (Maha raj et al.
2019); however, it is limited by nonspecific symptoms of the disease, including
weight loss, vomiting, nausea, heartburn, and fatigue, commonly seen in other
illnesses (Mansfield 2011).
Currently, the gold standard of clinical diagnosis is achieved by the pathological
analysis of the tumor tissue. Upper GI endoscopy, along with colonoscopy and
computed tomography, also helps make the diagnosis (Li et al. 2021a, b). The
treatment option relies on the stage and type of GI cancer. The traditional treatments
consist of surgical resection of the tumor, chemotherapy, radiotherapy, and their
combination. These methods have limited effects, and the prognosis has remained
low (Lu et al. 2020). For example, surgery is the first choice for colorectal, esophageal, and gastric cancers. Radiotherapy as neoadjuvant therapy can be used before
surgery to diminish the tumor size or kill the remaining cancer cells after surgery.
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However, using these methods, only 10–30% of esophageal and rectal cancer
patients show complete pathological response (Buckley et al. 2020).
Immunotherapy has become a revolutionary choice for treating cancers in the last
few decades. It consists of various methods to fight malignant tumors by inducing,
enhancing, or suppressing the immune responses (Mellman et al. 2011). There are
two types of immunotherapy: active and passive; active immunotherapy denotes a
patient’s immune system response (e.g., chimeric antigen receptor (CAR)-T cell
therapy and cancer vaccines), while passive immunotherapy refers to components
that are made out of the patient’s body (e.g., monoclonal antibodies) (Jeremy et al.
2016). Immunotherapy has shown fewer side effects and more efficacious results in
some GI cancers than conventional treatments. Immune checkpoint inhibitors (ICIs),
vaccine therapies, cytokine, and adoptive cell transfer (ACT) therapy are the main
types of immunotherapy for treating GI cancers (Dahiya et al. 2021). CAR-T cell
therapy is a type of ACT therapy that has advanced furthermost in clinical studies.
In this tactic, T cells are extracted from the patient’s bloodstream, genetically
engineered to express CARs, specified to recognize the tumor-associated antigens
(TAAs). The resultant T cells are then infused back into the patient (Bębnowska
et al. 2020). Numerous studies confirm the success of this method in hematologic
tumors; however, their performance in destroying solid tumors is under intense
investigation (Kang et al. 2021).
In this review, after a brief introduction to different types of immunotherapies, we
focus on the CAR-T cell method, its implication in GI cancers, its limitations, and
different strategies to overcome the obstacles.
2 Immune System
A healthy immune system can detect and kill tumor cells. However , numerous
regulatory factors, including immune cells, cytokines, and growth factors, intervene
in this process, which is disturbed in patients with can cer. The following sections
investigate the immune system’s response to the tumor.
2.1 Tumor Microenvironment (TME) Role in Immunotherapy
The tumor microenvironment (TME) is a complex tissue composed of tumor cells,
stromal cells, immune cells, as well as vasculature and extracellular matrices (ECM).
TME components have contrary effects on tumorigenesis, tumor progression, and
therapeutic resistance against immunotherapy (Zeng et al. 2021).
B lymphocytes have less described function in different types of GI cancers. They
can produce tumor-infiltrating plasma cells, which, by secreting antibodies, activate
cytotoxic cells, CD8+ T cells, and natural killer (NK) cells. B cells are also necessary
for activating T cells by acting as antigen-presenting cells (APCs) and contributing
to co-stimulatory signals. In this way, studies have shown that a higher infiltration
of CD138+ plasma cells is correlated with a better prognosis in colorectal and
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esophageal cancers (de Visser et al. 2005; DiLillo et al. 2010; Fristedt et al. 2016).
NK cells are a member of innate immune cells and present as the first-line defense
against malignant transformation. Downregulation of some NK receptors, including
NKG2D, NKp30, and NKp46, has been reported in pancreatic, colorectal, and
gastric cancer and is associated with disease progression and metastasis (Peng
et al. 2013). Macrophages play a significant and contrary role in tumor growth
regulation. For example, monocyte chemoattractant protein 1 (MCP-1), the
most crucial chemokine in summoning macrophages to TME, is associated with
tumor growth and is a negative immune regul ator in colon cancer (McClellan et al.
2012). Furthermore, tumor-associated macrophages consist of two groups:
M1-macrophages, which protect against tumor growth by secreting interleukin
(IL)-6 and IL-12, and M2-macrophages that are associated with tumor proliferation,
invasion, and metastasis. A higher M1/M2 ratio in TME of gastric cancer is
associated with a better prognosis (Pantano et al. 2013; Duque and Descoteaux
2014). T regulatory (T-reg) cells inhibit effector T cells, monocytes, and
macrophages by chemokine signaling. FOXP3 + T-regs have been reportedly
associated with progression and adverse stages of gastric cancer (Liu et al. 2019).
CD8+ T cells are the most powerful anti-tumor effectors and are the basis of current
immunotherapy techniques (Zhang et al. 2019a; b). Dendritic cells present antigenic
peptides to CD4+ T cells and activate effector T cells to respond against tumor cells.
Dendritic cell-based therapy with a high expression level of lymphocyte antigen-6E
(LY6E), a common protein in gastric and colorectal cancers, has shown promising
results in arousing cytotoxic lymphocyte responses (Ishigami et al. 2000;
Tokhanbigli et al. 2020). Cancer-associated fibroblasts secrete transforming growth
factor-beta (TGF-beta) and other growth factors, which cause the proliferation of
tumor cells and treatment resistance in GI cancers (Zhang et al. 2019a, b). Table 1
summarizes the role of some of the most important immune cells and cytokines in
TME in the progression or restraining of the tumor.
2.2 Cancer-Immunity Cycle
Our immune system, to some extent, can detect and remove tumor cells in a stepwise
manner described as the cancer-immunity cycle (Chen and Mellman 2013). This
cycle is expressed in seven steps: In the first step, APCs uptake dead tumor cells and
process them as antigens. The TAAs are then expressed on major histocompatibility
complex (MHC) classes I and II on APCs’ surfaces and are presented to T cells (step
2). Step 3 includes priming and activating T cells, enabling them to move to the
tumor’s location via the bloodstream (step 4) and invade the tumor bed (step 5).
T cell receptors (TCRs) recognize TAAs presented on MHCs and interact with them
(step 6), leading to the death of tumor cells (step 7). The release of TAAs from dead
cancer cells aids the restart of the cycle and summons more immune cells to the
tumor site. Each step is regulated by various factors (Chen and Mellman 2013; Aoki
et al. 2019; Wu et al. 2020). These regulatory factors may be disturbed in cancer
patients, allowing tumor cells to escape from immune cells. Immunotherapy, by
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Table 1 Role of TME components on tumor growth
Cells
B cells Inhibit Producing antibodies,
NK cells Inhibit Granzyme, perforin Zhang et al.
M1-macrophages Inhibit TNF-alpha, IL-6, IL-12 Duque and
M2-macrophages Activate IL-10, TGF-beta,
T-reg cells Activate IL-10, IL-35, TGB-beta van Herk and Te
CD8 T cells Inhibit Granzyme, perforin Zhang et al.
Dendritic cells Inhibit Antigenic peptides, IDO Ishigami et al.
CAFs Activate TGF-beta,
NK cells natural killer cells, T-reg, T-regulatory, CAF cancer-associated fibroblast, TNF-alpha
tumor necrosis factor-alpha, IL interleukin, TGF-beta transforming growth factor-beta, IDO
indoleamine-2,3-dioxygenase
Effects on
tumor cells
Cytokines and other factors
associated with these cells References
co-stimulatory signals
growth factors
growth factors
de Visser et al.
(2005)
(2019a, b)
Descoteaux (2014)
Duque and
Descoteaux (2014)
Velde (2016)
(2019a, b)
(2000)
Zhang et al.
(2019a, b)
regulating this cycle, optimizes the patient’s response to tumor removal (Chen and
Mellman 2013). For example, an immune checkpoint inhibitor, the programmed
death (PD) 1, is one of the most crucial proteins expressed on activated lymphocytes.
This protein can interact with its ligand (PD-L1) on cancer cells, blocking the
activation of T cells (Shah et al. 2019). Some advanced GI cancers, refractory to
standard treatment, have shown promising results following PD/PD-L1 inhibitors
(Xu et al. 2018; Antoniotti et al. 2020).
3 Types of Immunotherapies in GI Cancers
ICIs, vaccines therapy, and ACT are the most studied immunotherapies in GI
cancers (Dahiya et al. 2021).
3.1 Immune Checkpoint Inhibitors (ICIs)
In recent years, ICIs have shown much potential in treating different cancers.
Immune checkpoints are a group of cell surface receptors expressed by immune
cells to regulate T cell activation. In this way, cytotoxic T-lymphocyte-associated
protein-4 (CTLA-4) and its ligand (B7), as well as PD-1 and its ligand (PD-L1), are
two critical checkpoints that negatively regulate T cell activation (Shah et al. 2019).
The application of ICIs in advanced GI cancers has shown promising results. One
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