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the tumor-specific immune response. The antitumor immune response relies heavily
on DCs. DCs may present numerous TAA via MHC class I and II molecules as vital
APCs. They also play a crucial role in programming and regulating the antitumor
response by supplying the necessary co-stimulatory signals and guiding the production of cytokines. The goal of using viral antigen vaccines is to take advantage of the
virus’s pathogenicity to build a strong, tumor-specific immune response. Recombinant viral vectors benefit from producing any number of antigens while also delivering innate pro-inflammatory signals that boost the TAA-specific immune response.
Therapeutic immune vaccines have been tried in some different trials so far. In situ
vaccines have been tried on tumors with a lack of expressing T cells and peptide ones
to enhance cytotoxic T cells’ response. Immune vaccines get ready the immunity to
face cancer cells with educated responses (Kalyan et al. 2018; Bouzid et al. 2020).
Adoptive Cell Therapy
Adoptive cell therapy (ACT) is a cancer immunotherapy method that uses the
patient’s own lymphocytes to attack cancer cells. It acts as a stimulant and tries to
load autologous lymphocytes with cytokines or tumor antigens, then cultivates them
ex vivo before reinfusing them back into the patient. Cytokine-induced killer (CIK)
cells, tum or-infiltrating lymphocytes (TILs), natural killer (NK) cells, and CAR-T
cells are all examples of adoptive immunotherapy for HCC. Many investigations
have been conducted to determine the feasibility and safety of ACT in patients with
HCC, providing the groundwork for its therapeutic use (Jixia et al. 2017).
Conversion of Cold Tumors to Hot Tumors
Based on the recent classification, tumors are divided into two primary groups:
hot tumors with immunogenic microenvironments and cold tumors with
non-immunogenic ones. A considerable number of T-cell involvement with
increased PD-L1 expression on the tumor cells characterizes a hot tumor, whereas
a mild infiltration of immune cells characterizes a cold tumor. An increasing body of
research suggests that hot tumors react well to ICIs, but cool tumors do not. As a
result, in the case of cold tumors, combining ICIs with cancer vaccines, molecular
target therapies, or chemoradiation has the potential to cause cytotoxic T
lymphocytes infiltration and overexpression of PD-L1 on tumors, resulting in the
conversion of cold tumors to hot tumors; patients will then be followed by ICIs
therapy (Kono 2018).
Oncolytic Viruses
Oncolytic viruses are selectively reproduced in tumor cells and cause lysis without
damaging normal tissues. Oncolytic viruses’ anticancer efficacy is based on their
ability to destroy cancer cells directly by growing inside them and cell lysis
induction. Because the tumor’s defensive systems against viral infection are
impaired, most viruses may spread to a large extent in cancer cells. Tumor antigens
and viruses in cell lysates also trigger immune responses against cancer cells nearby.
Reoviruses, varicella viruses, and Sindbis viruses are examples of wild-type viruses
that exclusively infect tumors. These viruses initiate the first step to fight cancerous
Interdisciplinary Approach in Gastrointestinal Cancers 11
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cells. Next, engineering is used to remove viral genes that are required for replication
in normal cells but have no function in cancer cells. Furthermore, tumor-specific
promoters, such as the promoter of human telomerase reverse transcriptase, are used
before important viral genes in cancer cells to inhibit viral transcription in normal
cells. Viruses can then successfully targe t tumor cells after being modified by
TAA-specific receptors (Chiocca and Rabkin 2014).
6.2.2 Treatment Plans Based on Involved Organ
Esophagus Cancer
The esophagus is one of the most prevalent upper GI cancers, which could involve
other essential parts of the body due to its anatomical position. SCC is the most
common subtype, so most of the trials and studies are actively around it. Surgery and
resection along with radiotherapy and chemotherapy are authorized for these kinds
of cancers. Immune-related target therapies have also been approved for ICI
combinations recently. The combination of ipilimumab (anti-CTLA4 agent) and
nivolumab and pembrolizumab (anti-PD-1) were used in the SCC cases with
promising results. Recent developments in epigenetics and molecular studies have
led to specific genes and biomarkers discovery and peptide and DCs vaccines were
added to the immunotherapy treatment plans (Kono et al. 2018).
Gastric Cancer
Gastric cancer-approved treatment varies from case to case. Stomach surgery and
segmental and radical tumor resection were some of the first approved plans. In
advanced stages, radiotherapy and/or chemotherapy were added. In addition, radiation and target thera py by antibodies of HER2 and VEGF receptor 2 (VEGFR2)
were accepted for the patients. Immunotherapy got a trend in recent years with ICIs
as the center of attention. However, the results had a wide range from negative and
poor to non-sense and very effective. Other immunotherapies (monotherapy or
combination) that were tested through the years include immune vaccines, adoptive
cell transfer, and targeting specific receptors (OX40) by antibodies, which had
different prognoses. Also, CD73 expression was higher in gastric cancer versus
the healthy tissues. This persuaded researchers to try combination therapy for antiPD-1 and CD73 blockade (Sitarz et al. 2018).
Liver Cancer
HCC is the leader of the most lethal liver cancer subtypes. Treatment strategies of
liver cancer have a long history as well. First-line therapy for early stages is surgery
and resection, and in chronic liver failure, cirrhosis and fibrosis, indeed, a liver
transplant is the choice. Immune-related therapy is approved for liver cancer.
Targeting multi-kinase inhibitors and recently ICIs as the second-line for HCC
were approved. Also, immune vaccines and combinati on therapy had a high potential for enhancing the patients’ quality of life. As discussed, numerous types of
immunotherapy have been developed for HCC, the most promising of which is ICIs
targeting PD-1/PD-L1 and CTLA4. Most of the studies have investigated ICI-based
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medicines and other therapeutic techniques. Although ICI monotherapy protocols
have demonstrated advantages in certain HCC patients with generally acceptable
adverse events profiles, response rates (about 20%) have been unsatisfactory, owing
to the liver’s immunosuppressive qualities and the HCC tumor microenvironment
immunosuppressive features. Several sorts of combination strategies are now being
investigated in order to improve treatment effectiveness (Llovet et al. 2008).
Pancreatic Cancer
Pancreatic cancer overview for the upcoming 10 years is concerning. Ductal
carcinomas are the most common subtypes with more than 90% of all cases. The
main reason for poor prognosis and survival among the patients is weak modalities
and clues for diagnosing. The conventional approved therapies for these patients are
surgery (resection), chemotherapy, radiation, and immune-related targeted therapy
for EGFR inhibitors. ICIs monotherapy and combinations were a little controversial.
Although, in some trials, the combination of ICIs and chemotherapy and/or radiation
had effective results (McGuigan et al. 2018).
Colorectal Cancer
Rating among the top three cancer-related deaths, CRC’s approved strategies for
treatment consist of surgery for local, total, or radical resection, chemotherapy,
radiotherapy, and immune- related target therapy for antibodies against EGFR and
VEGF. Novel authorized immunotherapy is ICI, used in refractory dMMR/MSI-H
metastatic CRCs with effective results. MSI is described as a change in the microsatellite area inside tumor cells compared to normal cells. Microsatellites are short,
simple sequence DNA repeats. MSI findings for repeated unit insertion or deletion
were linked to DNA mismatch repair system problems. The MSI subgroup accounts
for about 15% of all CRCs. Its prevalence varies by stage. 15% of stage II–III CRCs
are dMMR, while only 4–5% of stage IV CRC cancers are dMMR. MSI-H status has
also been linked to a better overall prognosis as compared to individuals with
microsatellite stable CRC in recent years, MSS or pMMR (Schatoff et al. 2017).
Gallbladder Cancer
Intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder
cancer, and ampulla of Vater cancer are all examples of biliary tract malignancies,
a mixed collection of severe carcinomas. Chemo-resistance is increasingly common
in gallbladder cancer, necessitating novel therapeutic intervention measures.
Cholangiocarcinoma is among the rare cancers with a bleak outlook. The usual
approach to treat these cancers is surgical resection and adjuvant therapy such as
chemotherapy and radiation, but immunotherapy is a considerable strategy in many
cases (Rizzo et al. 2021). While being promising in some solid tumors, such as renal
cell carcinoma (RCC) and melanoma, the role of immunotherapy in biliary tract
cancer is n ot well defined, yet (Ahn and Bekaii-Saab 2019). In cholangiocarcinoma,
single-agent ICIs have had mixed outcomes, indicating modest but meaningful
responses in a small number of patients. In order to give more effective therapy
choices in advanced cholangiocarcinoma, novel combination tactics with ICIs are
now being investigated in this scenario (Rizzo et al. 2021).
Interdisciplinary Approach in Gastrointestinal Cancers 13
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6.2.3 Therapies Under Development
Combination therapy development has become a heated debate in recent years.
Some trials and evidence have shed light on the higher benefit of the combination
of immunotherapies, or immunotherapy with other conventional treatments than
monotherapy, such as immunotherapy-chemotherapy. Combination therapies can
open new gates to treat more advanced cancers later than first-line treatment. For
instance, the combination of anti-PD-1 antibody (nivolumab) and anti-CTLA-4
antibody (ipilimumab) is thought to be significantly more effective than
monotherapy for GI cancers (Overman et al. 2018). Studies over ICIs are still
progressing, and adoptive T-cell therapy and cancer vaccine are two interesting
topics for further GI cancer therapy development. CAR-T cell therapy with more
accurate target antigens is another active therapeutic study plan (Comoli et al. 2019).
Many new forms of such therapies, including blockade of LAG3, TIGIT, IDO,
CD47, or TIM3, are currently in the clinical development stage, the latter being a
receptor for HMGB1. Another hot topic is retaining the DNA associated with this
connection by triggering toll-like receptors (TLR) (Mazzarella et al. 2019). Studying
molecular mechanisms that promote immunosuppression, such as CD73, can be in
future therapeutic plans combination (Harvey et al. 2020). Novel immune vaccines
are targeting A2AR and CD73 and seem to have an effective resul t for GI cancer
patients (Harvey et al. 2020). TLRs are potential breakthroughs in immune-related
therapies. TLRs are expressed by various numbers of myeloid cells. They identify
the special molecular patterns of pathogen-associated molecules. The process of
signaling afterward activates the expression of inflammatory cytokines. All
conducted the way to activate the innate immune system. MEDI9197 is a TLR7
and TLR8 agonist that activates myeloid and lym phoid cells to produce
pro-inflammatory cytokines. New trials showed a bright vision of combination
therapy for MEDI9197 and ICIs, which improved the successful response
(Wilkinson and Leishman 2018).
7 Conclusion
Finding an efficient solution for reducing the heavy burden of GI cancers’ morbidity
and mortality is inquiring. Besides detecting occult blood in the fecal, specific
biomarkers such as CEA, CA19-9, supplementary imaging data like CTS and
ERCP, gene sequencing, and mole cular markers like PD-1/PD-L1 are proposed
diagnostic methods. According to the new studies, the diagnostic approach and
treatment plans have been established, but more suffered from low sensitivity and
specificity. New developments around the interdisciplinary data introduced some
immune checkpoint inhibitory agents such as anti-PD-1 (nivolumab) and antiCTLA-4 (ipilimumab) antibodies in special settings. Moreover, in advanced cancers,
combination therapy has been suggested for second-line therapy and later. Early
diagnosis and finding a more effective and convenient therapeutic plan are demanding and require more studies in the future.
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Acknowledgments The authors would like to acknowledge the help rendered by Dr. Zeinab Najafi
for providing her valuable comments.
Compliance with Ethical Standards The authors declare that there is no conflict of interest.
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Gastrointestinal Cancers: What Is the Real
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Board of Microenvironment and the Role
of Microbiota–Immunity Axis?
Edda Russo, Federico Boem, Lavinia Curini, and Amedeo Amedei
Abstract
The tumor microenvironment (TME) represents a complex and dynamic entity,
able to affect oncogenesis, tumor cells’ preservation, local invasion, and meta-
static propagation of gastrointestinal cancers. The TME is able to change
according to malignancy type, but common characteristics include immune
cells, blood vessels, stromal cells, and extracellular matrix. Moreo ver, emerging
evidence includes also the gut microbiome (GM) in the TME and, in particular, its
mutual interplay with the immune response (named microbiome–immunity axis),
in gastrointestinal cancers. In this scenario, the reciprocal interaction between
cancer cells, immune system, and GM leads to new thinking on the TME borders’
redefinition in the field of gastrointestinal cancers. In this chapter, we retraced the
most important studies on the crosstalk between microbiome (and its metabolites)
and immune response, and how it affects the TME of gastrointestinal cancers. We
discussed the multiple layers of the TME within the holobiont vision and exam-
ined how microbial dysbiosis could influence the mutual relationship between the
host immunology and GM in several districts of the gastrointestinal tract, affect-
ing oncogenesis, tumor progression, and response to immunotherapy treatment.
A deep understanding of all the actors and dynamics of TME in the gastrointesti-
nal tract will allow the design of more effective and tailored therapies, able to
target specific TME levels and components, associated with the malignancy
development and progression.
E. Russo · L. Curini · A. Amedei (*)
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
e-mail: amedeo.amedei@unifi.it
F. Boem
Philosophy and Technology Section (PHIL), University of Twente (NL), Enschede, Netherlands
#
The Author(s), under exclusive license to Springer Nature Switzerland AG 2022
Interdisciplinary Cancer Research, https://doi.org/10.1007/16833_2022_6
Published online: 20 August 2022
17
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Keywords
Gastrointestinal cancer · Immune response · Immunity · Immunotherapy ·
Microbiome · Microbiota · Tumor microenvironment
1 Introduction
Digestive tumors are malignant conditions of the gastrointestinal (GI) system and
accessory digestion organs (esophagus, biliary system stomach, small intestine, large
intestine, rectum, pancreas, and anus). The general symptoms can include obstruction, abnormal bleeding, and different associated problems. Gastrointestinal tract
(GIT) cancers represent a significant portion of the global health-care burden
(Arnold et al. 2020), and, according to their prevalence, colon (CRC), stomach,
and liver cancers are the main concerns within this group (fourth, sixth, and sevent h
most prevalent, respectively). The principal causes of death are stomach cancer
(second highest), liver cancer (third highest), and CRC (fifth highest) (Russo et al.
2019). Even though it is not one of the top 10 most common cancers, pancreatic
ductal adenocarcinoma (PDAC) has some of the worst prognoses and is presumed to
be one of the leading causes of death from cancer by 2030 (Rahib et al. 2014).
Furthermore, esophageal cancer is common in some countries (Bray et al. 2018).
The multistep biological mechanisms acting in the prevention and development
of GI cancer are still largely unknown, which is why GI cancers are thought to be a
multifactorial disease caused by complex interactions between genetic factors,
epigenetic changes, immune function, environment elements (including geographic
area and socioeconomic status), way of life, and nutrition.
The majority of GI cancer investigations and therapeutic strategies have mainly
concentrated on cell-autonomou s processes in the epithelial compartment. Indeed,
tumor cells trigger important molecular, cellular, and physical alteration within their
host tissues. Nevertheless, there is mounting in vivo evidence that epithelial cells
react to their “microenvironment.” Indeed, the emerging tumor microenvironment
(TME) represents an intricate and ever-changing entity. TME patterns vary
according to malignancy type, but common characteristics include immune cells,
blood vessels, stromal cells, and extracellular matrix (ECM). The TME is a dynamic
“influencer” of tumor development; in fact, a mutual relationship is created between
cancer cells and TME elements in early oncogenesis to promote tumor cell preservation, local invasion, and metastatic propagation. Moreover, the TME coordinates a
molecular system that fosters angiogenesis, to re-establish oxygen/nutrient source
and remove metabolic waste, in order to overcome a hypoxic and acidic microenvironment. In addition, cancers are infiltrated by a variety of adaptive and innate
immune cells that can have both pro- and antitumorigenic impact (An derson and
Simon 2020). Finally, another critical feature of this complex network in GI cancers
is the luminal content, particularly the gut microbiome (GM); its implications on
immunity and tumorigenesis are only just beginning to be recognized (Fig. 1) (Russo
et al. 2016). Nevertheless, all the abovementioned factors could influence GI
Gastrointestinal Cancers: What Is the Real Board of Microenvironment.. . 19
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Fig. 1 The GI microbiota and immune system interact in a complex network with the cancer cells
through a TME modulation. The GI microbiota can influence TME and thus tumor growth in both a
positive or negative way and can also modulate the immune responses. Cancer growth is inhibited
by the host immune system, which can be stimulated by the GI bacteria. Cancer can affect the host
immunity by activating immunosuppressive pathways and can also modulate the GI flora
microbiota, changing its structure and functions during cancer development
(Vivarelli et al. 2019). In healthy individuals, GI microflora acts as a symbiont,
protecting against invading pathogens and avoiding cancer development (Pickard
et al. 2017). When the fine equilibrium of this commensal bacterial community is
destroyed, a dysbiosis state can develop, which can lead to pathological processes in
the host, such as cancer (Cugini et al. 2021). Finally, increasing data on the TME
physiology has suggested new targets within to improve cancer alternative therapies.
In this chapter, we would like to reconsider the TME state of the art to define its
boards within the holobiont (defined as the assemblage of a host and the many other
species living in or around it, which together form a discrete ecological unit) vision
and to assess its interaction with microbiota and their reciprocal influence in GI
cancers. We will discuss how disequilibria (dysbiosis) could influence the mutual
relationship between the host immunity and intestinal bacteria affecting oncogenesis, tumor progression, and response to immunotherapy treatment.
2 The Borders of GIT Microenvironment
In the past, tumors have traditionally been considered genetic disorders, which
means that the main approach in the field of oncology, especially after the
innovations brought by the molecular turn in biomedicine, has been to identify the
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