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Role of Neuromodulators in Regulation of the Tumor Microenvironment.. . 185
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The Role of Tumor Microenvironment
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in Colon Cancer
Caterina Fattorini, Marco Arganini, Andrea Cavazzana,
and Maria Raffaella Ambrosio
Abstract
Colorectal cancer (CRC) is one of the most common causes of morbidity and
mortality in both women and men. Given that CRC is an important health
problem, many efforts have been spent to better stratify patients in terms of
prognosis and prediction of respon se to therapy. In recent years, the tumor
microenvironment (TME) has received increasing attention by scientific commu-
nity; many research focused on its possible prognostic and predictive role. Here
we aim to summarize the latest available knowledge in this field through a
literature research and to highlight possible critical issues and opportunities.
The most relevant studies highlighted the crucial role of TME in cancer develop-
ment and progression. The immune compartment above all is an important
prognostic factor. In fact, a brisk peri- and intratumoral inflammatory response
is associated with better survival, while low immune infiltrates are a sign of poor
outcome. Investigators comparing hematoxylin-eosin tumor-infiltrating lympho-
cyte evaluation and immunohistochemical lymphocytic subset studies came to
stackable conclusions. To enter immune cells’ assessment in routine clinical
practice, previous studies focused on possible standardized scores such as
Immunoscore® and tumor-stroma ratio. Moreover, recent groups implemented
manual cell count with digital image analysis software. Finally, components of
TME are also promising therapeutic targets: antiang iogenetic agents and immu-
notherapy are now routinely available and agents directed against other TME
components such as cancer-associated fibroblasts are under study. The role of
C. Fattorini · A. Cavazzana · M. R. Ambrosio (*)
Pathology Unit, Azienda Sanitaria Toscana Nord-Ovest, Pisa, Italy
e-mail: maradot@libero.it
M. Arganini
Surgery Unit, Ospedale Unico Versilia and Nuovo Ospedale Apuane, Azienda Sanitaria Toscana
Nord Ovest, Pisa, Italy
#
The Author(s), under exclusive license to Springer Nature Switzerland AG 2022
Interdisciplinary Cancer Research, https://doi.org/10.1007/16833_2022_26
Published online: 12 October 2022
187
188 C. Fattorini et al.
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TME in CRC progression and prognosis has been widely recognized. However,
there is a lack of standardization regarding immune infiltrates’ assessment that
would make it incorporable in routine clinical practice. Moreover, the role of
digital pathology in TME evaluation is currently under studies and the true
cost-benefit ratio of new technologies is not yet fully elucidated. Finally, further
research would lead to novel therapeutic strategies.
Keywords
Colorectal cancer · Inflammatory response · Tumor microenvironment
1 Introduction
Colorectal cancer is one of the commonest cancers occurring in both women and
men, ranking third in terms of new cases, preceded by breast and lung cancer, and
second for mortality after lung cancer in 2020 (Global Cancer Observatory 2020).
CRC incidence and mortality rates greatly vary from country to country according to
Human Development Index (HDI). The highest incidence occurs in high HDI
countries (Europe, Australia, and Northern America mainly), and this fact is strongly
related to CRC risk factors: countries with higher population level of obesity, red
meat consumption, alcohol consumption, sedentary lifestyle, and tobacco use are at
the higher risk of developing CRC. The mean age at diagnosis is 68 years for men
and 72 years for women. However, in the last years, an increased incidence has been
observed in patients younger than 50 years (Sawicki et al. 2021).
Considering these data, CRC is indeed an important health problem and during
the last decades, a lot of efforts have been made to improve diagnosis and prognosis.
Prognostic stratification of patients is mainly based on a correct staging following the
TNM staging system (Amin et al. 2017); the most relevant pathological parameters
taken into consideration are depth of tumor invasion (T) and presence/absence of
lymph nodes (N) and distant (M) metastasis. Other important prognostic factors
that guide treatment decisions are lymphovascular and perineural invasion, the state
of resection margins, microsatellite instability, and KRAS/NRAS/BRAF mutation
status.
Scientists’ attention has recently focused on tumor microenvironment as an
important host factor that seems to play a crucial role in CRC progression; these
studies allow clinicians to better stratify patients’ outcome and guide therapy (Liu
et al. 2020 ).
Tumor microenvironment (TME) is the complex background where the tumor
settles and grows, and it consists of all cellular and noncellular components that have
close interaction with tumor cells. The cellular component of TME is composed
mainly of endothelial cells and pericytes that form blood vessels, immune cells, and
stromal cells such as fibroblasts, whereas noncellular component consists of extracellular matrix (ECM) and signaling molecules such as cytokines (Baghban et al.
2020).
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In this chapter, we will focus on the main components of tumor microenvironment in colorectal cancer and their role in promoting tumorigenesis and cancer
progression; afterward, we will take into consideration the latest technologies used
for TME analysis as well as the therapeutic implications of TME in colorectal
cancer.
2 TME and Colorectal Cancer
Tumor microenvironment is now widely recognized as an important host factor in
determining patient treatment response and survival (Alexander et al. 2020). Both
tumor-infiltrating immune cells and stroma cells contribute to determine the clinical
behavior of the neoplasia. The first studies of peritumoral immune infiltrates in
colorectal cancer patients date back to the 1960s, when Spratt and colleagues first
took into consideration TME as a variable influencing prognosis (Spratt and Spjut
1967). Since that time, the role of TME has been extensively studied, especially the
immune compartment.
3 Immune Cellular Compartment of TME
Scientists have generally reported that a brisk inflammatory cell infiltrate within
and around tumor cells was associated with improved clinical outcome, and it was
thought to be the host immune response to the tumo r (Murray et al. 1975; Watt and
House 1978; House and Watt 1979; Svennevig et al. 1984). Subsequently, studies
had focused on determining the density and composition of immune infiltrate of
TME, trying to find a connection between lymphocyte and macrophage subsets and
outcome. Various methods of assessment of immune infiltrates on hematoxylin and
eosin (H&E) sections have been developed over time: immuno-scores, Crohn’s-like
reaction evaluation, tumor-infiltrating lymphocyte studies, and combined
assessments. Moreover, many scientists focused on the characterization of lymphocytic subpopulations.
3.1 Jass and Klintrup-Makinen Scores
One of the first and most important work was the ones carried out by Jass and
colleagues in 1986 and by Klintrup and coworkers in 2005 that both ended up
becoming important semiquantitative scores. Jass and coworkers evaluated immune
infiltrates at the invasive margin (IM) and developed a three-point scale: pronounced, moderate, and little. A pronounced infiltrate appeared to be an independent
prognostic factor and allowed scientists to stratify patients’ survival (Jass 1986).
Subsequently, in 2005, Klintrup and colleagues developed the Klintrup-Makinen
(KM) score: they also evaluated infiltrates at the invasive front and in the areas of
deepest invasion. Overall, inflammatory reaction and the amount of lymphoid cells
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and neutrophilic and eosinophilic granulocytes were assessed by using a four-degree
scale. A score of 0 indicated an absence of reaction, 1 weak, 2 moderate, and 3 severe
increase of each cell type. A similar scale was used at the invasive margin. A score of
0 was given when there was no increase of inflammatory cells, 1 denoted mild and
patchy increase of inflammatory cells at the invasive margin, but no destruction of
invading cancer cell islets by the inflammatory cells. A score of 2 was given when
inflammatory cells formed a band-like infiltrate at the invasive margin with some
destruction of cancer cell islets by inflammatory cells. A score of 3 denoted a very
prominent inflammatory reaction, forming a cuplike zone at the invasive margin, and
destruction of cancer cell islets was frequent and invariably present. Examples of
moderate and severe immune infiltrates can be noted in Fig. 1. Macrophage reaction
Fig. 1 Hematoxylin-eosin slides representing lymphocytic immune infiltrate examples in colonic
adenocarcinoma at 20× magnification. (a) and (b) Peritumoral immune infiltrate of moderate
density arranged at invasive tumor margin. (c) and (d) A brisk lymphocytic infiltrate encircled
neoplastic glands
The Role of Tumor Microenvironment in Colon Cancer 191
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was graded as either absent (grade 0) or present (grade 1). Macrophage reaction
was recorded as being present when collections of foamy macrophages encircling
invading tumor islets were observed, and as being absent when such collections
of macrophages were not observed (Klintrup et al. 2005). Simi larly to Jass, they
concluded that high-grade inflammation was an independent prognostic factor in
colorectal cancer.
3.2 Crohn’s-Like Reaction
Graham and colleagues analyzed the presence of discrete lymphoid aggregates with
or without germinal centers beyond the advancing tumor front of 100 colorectal
cancers (Graham and Appelman 1990). This type of peritumoral immune infiltration
was called “Crohn’s disease-like reaction (CLR)” because of the similarities with the
reactive infiltrates of Crohn’s disease, and it was mainly located in muscularis
propria or pericolic fat tissue. The intensity of this reaction was graded as absent,
mild, or intense. They also evaluated the presence of invasion beyond the tonic
muscularis propria, nodal metastases, and lymphoid infiltrates at tumor margins;
moreover, they correlated CLR with survival. Graham and colleagues concluded that
CLR happened more frequently in right-sided cancer that invaded muscularis propria
and pericolic fat. They also noted that an intense CLR was associated with a high
immune infiltrate at tumor margin, a lower incidence of nodal metastases, and a
statistically significant increase in 10-year survival rate. They hypothesized that CLR
represented a part of the favorab le host response together with TILs at invasive
tumor margin.
In 2013, Ueno and colleagues analyzed more than 1000 colorectal cancers and
proposed a new way of CLR evaluation, revising the “Graham method”: they noted
the total number of lymphoid aggregates (LA) observed in all tumor slides per case,
the average number of LA per slide, and the number of LAs in a ×2 microscopic
objective lens field where CLR was most intense; moreover, they determined the
diameter of the largest LA. Based on their results, they concluded that there was no
significant correlation between the number and recurrence rate or 5-year diseasespecific survival rate. In contrast, they found that the size of LA was important: LA
with a diameter larger or equal to 1 mm were associated with lower recurrence rate
and higher 5-year disease-specific survival rate, and they had an independent impact
on survival from T stage, N stage, or tum or buddin g (Ue no et al. 2013).
Also Vayrynen and coworkers revised the Graham method: they not only counted
the number of CLR follicles but also the length of the invasive front. Then they
defined a new parameter, called “CLR density,” which is the number of CLR
follicles/the length of the invasive front. Also the number of lymphoid follicles
with germinal centers, the average diameter of the lymphoid follicles, and the
histological layer with the highest concentration of lymphoid follicles were
annotated. Finally, they include the qualitative criteria of Graham in CLR evaluation
as follows: 0 (no reaction) denoting no or at most one single lymphoid aggregate in
all tumor sections, 1 (mild reaction) defined as occasional lymphoid aggregates with
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rare or absent germinal centers, and 2 (intense reaction) denoting numerous lymphoid aggregates with germinal centers. Statistical analysis revealed that high CLR
density was associated with low stage, mismatch repair deficiency, and high
peritumoral and intratumoral T-cell infiltrates; moreover, high CLR density was a
stage independent marker of better survival rate. Scientists concluded that their new
parameter, the so-called CLR density, was superior to Graham method for CLR
evaluation, allowing a better patient stratification.
3.3 TIL Evaluation on H&E
TILs are the main component of the immune cell infiltrate of TME. TILs comprise
T-lymphocytes, B-lymphocytes, and also NK cells and have been shown to have
important prognostic value in colorectal cancer (Hendry et al. 2017). Both
intratumoral (IT) TILs and TILs at the invasive margin (IM) of tumors have been
evaluated. Invasive margin was defined as an interface between the host stroma and
the invading edge area of a tumor (Klintrup et al. 2005). Many scientists evaluated
the role of B- and T-lymphocytes in TME, and most part of studies found a positive
association with survival using Klintrup-Makinen score (Ogino et al. 2009; Hynes
et al. 2017 ; Ropponen et al. 1997; Iseki et al. 2018; Rozek et al. 2016).
3.4 Combined Assessment
In 2009, Ogino and coworkers developed a combined scoring system taking into
consideration Klintrup-Makinen score, Crohn’s-like reaction, and intratumoral and
peritumoral TIL evaluation (Ogino et al. 2009). They analyzed more than 800 colorectal cancers and assigned a semiquantitative score to each element and then
combined them in a total score called “overall lymphocytic reaction score.” Based
on an arbitrary cutoff, they separated the cohort into three catego ries and then related
the results to survival data. They founded that all elements except intratumoral TILs
were statistically significant for overall survival (OS) regardless of other clinical,
pathological, or molecular characteristics; in particular, a high overall lymphocytic
score was associated with higher OS compared to patients with low immune
infiltrates.
3.5 Immune Cell Subsets
Scientists have also focused on subset characterization of immune cells,
B-lymphocytes, T-lymphocytes, and NK cells, in particular, and their relationship
with survival data. CD20 is used as a B-lymphocyte marker, while CD3 is a
pan-T cell marker and CD56 is the marker of NK cells. T-lymphocytes are
subdivided in CD4+ helper T-cells (Th cells), CD8+ cytotoxic T-cells, FOXP3+
regulatory T-cells (Treg), CD45RO+ memory T-cells, and PD1+ CD8+ T-cells
(namely, exhausted T-cells).
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One of the principal works on immune cell infiltrate characterization in colorectal
cancer was that of Galon and colleagues (Galon et al. 2006). They performed a
combined genomic and immunohistochemical (IHC) study of more than 400 colorectal cancer patients. They evaluated the expression level of genes related to
inflammation and the composition of the adaptive immune response to tumors by
using immunohistochemical markers of different lymphocyte subpopulations: CD3-,
CD8-, and CD45RO-positive cells’ density at the center of tumor (CT) and the
invasive margin (IM). Then Galon and coworkers related IHC and genomic results to
patients’ outcome. They concluded that type, location, and density of immune
adaptive response had a prognostic value: both disease-free survival (DFS) and OS
rates were higher for patients with high density of CD3-, CD8-, and CD45ROpositive cells at IM and CT.
Some other investigated the role of single markers:
• CD3 is a pan T-cell marker. Most studies found a significant positive association
between CD3+ cell number and survival (Sinicrope et al. 2009; Galon et al. 2006;
Guidoboni et al. 2001; Flaher ty et al. 2016; Laghi et al. 2009; Deschoolmeester
et al. 2010; Berntsson et al. 2017; Nearchou et al. 2019). Some others instead
didn’t find any significant association with survival (Lavotshkin et al. 2015;
Hanke et al. 2015; Schweiger et al. 2016).
• CD8 is a cytotoxic T- cell marker. The role of cytotoxic cells is mainly to
recognize a foreign antigen, induce cell lysis, and recruit other immune cells
via cytokine production (Alexander et al. 2020). Many authors found that higher
CD8+ cell-rich immune infiltrates were associated with better survival (Menon
et al. 2004; Prizment et al. 2017; Chiba et al. 2004; Flaherty et al. 2016;
Guidoboni et al. 2001; Deschoolmeester et al. 2010; Eriksen et al. 2018; Katz
et al. 2009). However, other scientists didn’t find that association (Takemoto et al.
2004; Baeten et al. 2006; Suzuki et al. 2010).
• CD4 is a surface marker expressed by helper T-cells, which plays a role in
anticancer immunity by having cytotoxic capabilities and also by recruiting
cytotoxic T- and B-cells (Borst et al. 2018). In most cases, scientists found a
positive association between density of CD4+ cells and survival data (Chen et al.
2016; Ling et al.
2004; Nagtegaal et al. 2001 ; Lavotshkin et al. 2015; Matsutani et al. 2018).
• CD45RO is a surface marker expressed especially by effector memory T-cells.
These types of cells enact a swift response to a recognized foreign antigen
(Mahnke et al. 2013). Also for that marker, studies tended to find a correlation
between expression and survival (Kim et al. 2015; Chen et al. 2016; Richards
et al. 2014; Pagès et al. 2009).
• FOXP3 is expressed by regulatory T-cells, whose role is to regulate the immune
system by suppressing T-cell activity and preventing overactivity and autoim-
mune events (Alexander et al. 2020). Some scientists theorize that regulatory
T-cells may have a negative effect on survival because of their anti-immune effect
and some studi es seem to corroborate this theory, other works instead found a
positive association with survival (Kim et al. 2015; Chen et al. 2016; Ling et al.
2014; Canna et al. 2005), while in some cases not (Menon et al.
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2014; Miller et al. 2017; Salama et al. 2009; Nosho et al. 2010; Märkl et al. 2017)
or they didn’t find it at all (Mori et al. 2015; Loddenkemper et al. 2006; Chen and
Chen 2014). Surely further studies are needed to elucidate the exact role of
FOXP3+ cells in colorectal cancer TME.
• PD-1+ CD8+ T-cells: these types of cells are also known as “exhausted T-cells.”
The concept of “T-cell exhaustion” was born a few years ago. Wherry defined
T-cell exhaustion as a state of T-cell dysfunction that arises during chronic
infections and cancer (Wherry 2011). Poor effector function, sustained expression
of inhibitory receptors, and a transcriptional state distinct from that of functional
effector or memory T cells characterize exhausted T-cells. In particular, when
chronically stimulated, CD8+ effector (cytotoxic) T-cells progressively lose their
functions: firstly, there is a reduced expression of pro-inflammatory cytokines that
causes a loss of effector T-cell proliferation capacity; then these cells acquire
PD-1 membranous expression; afterward, they lose their cytolytic function; the
result of all these steps is the deletion of CD8+ PD-1+ effector T-cells, namely, a
“T-cell exhaustion.” In tumor context, T-cell exhaustion can lead to premature
cessation of the immune response against neoplasia. The expression of PD-1
seems to be a crucial event in T-cell exhaustion process; because of this, scientists
theorized that cancer patients with active immune infiltrates can benefit from
immune check point inhibitors. In fact, PD-1 inhibition would be able to return
CD8+ PD-1+ effector T-cells on a functional state. Several studies have been
conducted on exhausted T-cells in colon cancer. For example, Prall and Hühns
analyzed PD-1 expression of T-cells in CRC microenvironment by using CD8,
granzyme B, FoxP3, CD68, S100, and PD-1 immunohistochemistry (Prall and
Hühns 2017). The density of every immune cell subtype was calculated and then
a hierarchical clusterization was made. They found three different groups
representing different types of immune microenvironment: an “immunoreactive”
group with numerous PD-1+ cells, an “anergic/immune-naive” group, and an
“intermediate” group. Furthermore, they concluded that the immunoreactive
group has not only an active host anti-tumor response but also an undercurrent
T-cell exhaustion mechanism. The identification of such immune type of cells in
CRC microenvironment can possibly have clinical and therapeutical implications,
and further studies are certainly needed to carefully evaluate the role of check-
point inhibitors in this category of patients.
• CD20 is a pan B-cell marker; B-lymphocytes interact with T-cells, produce
cytokines to recruit and activate T-cells, and then act as antigen-presenting cells
(APC) and produce antibodies (Tsou et al. 2016). There are only a few studies
examining the expression and role of CD20+ cells in CRC, and most of them
found a positive association between CD20 expression and survival (Chen et al.
2016; Meshcheryakova et al. 2014; Berntsson et al. 2016 ; Edin et al. 2019).
• CD56/CD57 are NK cell markers, whose role is to induce cell lysis (Vivier et al.
2008). Most part of the few available studies found a positive association with
survival considering both IM and IT (Menon et al. 2004; Coca et al. 1997;
Tachibana et al. 2005; Liska et al. 2012
).
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