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The Role of Tumor Microenvironment in Colon Cancer 195
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Despite the results of all these studies examining the impact of single immune cell
subsets on outcome, a semiquantitative H&E evaluation of immune infiltrates seems
to be enough for a correct assessment of inflammatory infiltrates, given that it
provides similar prognostic results (Alexander et al. 2020).
3.6 TAMs (Tumor-Associated Macrophages)
Tumor-associated macrophages are monocyte deputies to phagocytosis, antigen
presentation, and T-cell recruiting. Their role in cancer progression is still not fully
known. Many studies have highlighted a dual role of TAM within TME: these cells
have both pro-tumor (Wang et al. 2021b) and anti-tumor properties (Pernot et al.
2014). TAMs are subdivided into two categories: M1 and M2 cells. M1 TAMs are
known for their role in contrasting tumor progression, while M2 TAMs are believed
to have a pro-tumor role. CD68 is a generic macrophages marker, while CD163 and
CD206 are more specific for M2 macrophages. Using these antibodies, investigators
analyzed the density of M1 and M2 TAMs in CRC. Most studies found that the
presence of M2 cells was generally associated with a worse outcome, while high M1
count was related to better prognosis (Edin et al. 2012).
When considering both M1 and M2 density together, the anti-tumor effect seems
to prevail since available studies highlighted their positive association with survival.
For example, two studies (Li et al. 2017; Forssell et al. 2007) found that high density
of TAM at tumor front was associated with more TIL count, less epithelialmesenchymal transition (EMT) markers, fewer tumor buds, and finally longer OS.
3.7 TANs (Tumor-Associated Neutrophils)
Neutrophils are an essential component of the innate immune system. They normally
induce phagocytosis, release lytic enzymes, and contribute to produce ROS. Like
TAMs, TANs also polarize toward two distinct phenotypes in response to environmental signals: N1 neutrophils that have antitumorigenic properties and N2
neutrophils, with pro-tumorigenic activity. N1 cells increase cytotoxicity and produce various numbers of molecules, such as TNF-alfa, ROS, and Fas that reduce
immunosuppressive abilities. N2 cells instead support tumor progre ssion and invasion via production of many factors such as VEGF, MMP9, and CCL5 and also by
capturing circulating tumor cells and promoting their migration to distant sites
(Mizuno et al. 2019). It seems that the levels of TGF-beta inside the tumor determine
neutrophil polarization: high TGF-beta levels promote N2 differentiation, while low
levels promote N1 polarization.
The role of TANs in CRC is still not yet clear, since studies highlighted
conflicting results. For example, Rao and colleagues found that a high density of
TANs was associated with worse survival (Rao et al. 2012), while Berry and
coworkers noted a better survival (Berry et al. 2017).
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4 Stromal Cellular Compartment of TME
4.1 Cancer-Associated Fibroblasts (CAFs)
Cancer-associated fibroblasts are the main component of the stromal compartment of
TME (Pietras and Ostman 2010). Physiologically, fibroblasts are cells of connective
tissue with elongated morphology and negativity for epithelial, endothelial, or
leukocyte markers and the main producers of extracellular matrix (ECM); they
also have an important role in tissue repair processes. Fibroblasts normally produce
various numbers of substances including TGF-beta, which favors the acquisition of a
myofibroblast phenotype; VEGF-alfa, which promotes angiogenesis; and numerous
chemokines and cytokines. Fibroblasts also play a role in immune system regulation,
by promoting immun o-tolerance processes. CAFs are a distinct population of
fibroblasts with unique characteristics that actively interact with neighboring cancer
cells and originate from local stromal fibroblasts. According to some studies, the
contact between fibroblasts and tumor cells would stimulate the production of
TGF-beta and other mediators that promote the expression of alfa-SMA, the activity
of the contractile cytoskeleton, and the activation of JAK-STAT signaling pathway,
finally driving the acquisition of a CAF phenotype. Also genomic alterations like
double-strand breaks are able to promote the transformation of fibroblasts into CAFs
(Sahai et al. 2020 ).
CAFs perform multiple functions: they are in charge of ECM remodeling,
enzyme production, and tumor stiffness promotion. Mechanical alteration of
peritumoral stromal compartment could lead to blood vessel collapsing, to hypoxia,
and subsequently to increased invasion capabilities. They also promote angiogenesis
via VEGF production and are able to influence the immune compartment: various
chemokines and cytokines produce d by CAFs have important immunosuppressive
or immunopromoting effects on CD8+ T-cells, regulatory T-cells, and macrophages
(Sahai et al. 2020). Moreover, through CXCL5 secretion, CAFs promote PD-L1
expression in cancer cells (Deng et al. 2021).
The role of CAF in CRC has been widely investigated but nowadays study results
are conflicting. Tsujino and coworkers studied the role of myofibroblasts in CRC,
considering alfa-SMA as a marker, and found that tumors with abundant
myofibroblasts were associated with shorter DFS (Tsujino et al. 2007). In 2013,
Choi and colleagues analyzed various CAF subpopulations using various immunohistochemical markers and their prognostic significance in CRC. They noted that
podoplanin+ CAFs were associated with less aggressive tumors and more favorable
prognosis; on the contrary, alfa-smo oth muscle actin (SMA)+/podoplanin- and
S100+/podoplanin- fibroblasts were associated with tumor progression (Choi et al.
2013). Another study analyzed the combined role of CAF and M2 TAMs (Herrera
et al. 2013): the expression of CAF and M2 macrophages was related to patients’
survival; in particular, FAP marker was associated with poorer survival. Son and
coworkers instead found that immature CAFs located at the invasive tumor front
were a favorable prognostic factor (Son et al. 2019).
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Finally, recent studies found that an almost total depletion of CAFs within TME
results in more aggressive tumors (McAndrews et al. 2021); in particular, a selective
depletion of alfa-SMA+ CAFs in genetic mouse models resulted in increased tumor
invasiveness capabilities and reduced OS.
It is therefore clear that further studies are needed to clarify CAFs’ role in CRC.
5 TME and Mismatch Repair System
The genetic pathways through which CRC develops are mainly three: subseq uent
mutations in APC/TP53/KRAS that lead to the classic adenoma-carcinoma
sequence; chromosomal instability, in which tumor suppressor g enes are silenced
by promoter methylation; and finally the microsatellite instability (MSI) pathway,
characterized by alteration of mismatch repair system. The latter type of CRC is
defined as deficient mismatch repair (dMMR) or MSI cancers, and they represent
10% of all CRC and occur due to mutations in MMR genes and subsequently the loss
of repair functions of one or several MMR proteins, in particular MLH1, MSH2,
MSH6, and PMS2. MSI tumors are usually characterized by a distinct morpho logy:
right sided, an abundant immune infiltrate (high TIL count and brisk Crohn’s-like
lymphocytic reaction), medullary morphology, or mucinous/signet-ring cell differentiation. Mismatch repair-deficient tumors can be sporadic or associated with
Lynch syndrome, an inherited syndrome that predisposes to develop numerous
tumors, including colorectal cancer. For this reason, it is very important to identify
Lynch syndrome patients and subsequently test their family members. In most cases,
sporadic dMMR tumors are caused by acquired methylation of MLH1 promoter
leading to MLH1 and PMS2 production loss. Moreover, 50% of sporadic MSI
tumors carry the BRAF V600E mutation. Instead, inherited cases are mainly due
to germline mutations of MSH2, PMS2, or MSH2 genes, leading to MSH2/MSH6
combined loss or MSH6 or PMS2 isolated loss, and are not characterized by BRAF
mutations (Samowitz 2015).
Morphologic characteristics are able to suggest microsatellite status; in particular,
TIL count on H&E can predict MSI status with a specificity between 62% and 97%
and a sensitivity between 21% and 93%. For this reason, in the past years, scientists
used TILs as a screening test for MSI; in fact, a few years ago, MSI genetic testing
was expensive, so clinician needed to selectively test patients. However, now, with
the advent of immunohistochemical testing for DNA mismatch repair proteins,
according to the latest National Comprehensive Cancer Guidelines, screening for
MSS/MSI status is recommended for all CRC cases (Hendry et al. 2017). If there is a
loss of one or more proteins detected with ICH testing, then a BRAF gene mutation
status test is recommended to identify BRAF V600E-negative tumors as a screening
for possible Lynch syndrome-associated tumors. In Fig. 2 is represented a case of
MSI CRC tumor with loss of MSH6 protein immunohistochemical expression (see
below).
The main reason behind high TIL infiltration in MSI colorectal cancers is that
dMMR are known to be immunogenic and neoantigen bearing (Phillips et al. 2004).
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Fig. 2 Colonic adenocarcinoma dMMR. (a) and (b) A representative area for MMR protein
evaluation in a colic adenocarcinoma (H&E slides, 5× magnification in (a) and 10× in (b)).
(c) Complete loss of MSH6 protein expression in adenocarcinoma glands is a clue of microsatellite
instability (MSH6 stain, 10× magnification). (d)–(f) Respectively, MSH2- (d), PMS2- (e), and
MLH1- (f) positive immunostain in cancer glands (original magnification 10×)
Accordingly, MSI tumors are characterized by a high tumor mutational burden
(TMB): hypermethylation, BRAF mutations, and mismatch repair protein gene
encoding DNA are responsible for the presence of neo-antigens and subsequently
for an abundant immune infiltrate. In fact, a high TMB causes an increased expression of MHC-I molecules and the subsequent differentiation of T-cells in CD8+
cytotoxic T-lymphocytes. Moreover, it increases the efficiency of antigen-presenting
cells (APCs) and upregulates MHC-II molecules causing CD4+ helper T-cells to
activate other immune cells (Bai et al. 2021). Furthermore, the high TIL recruitment
of MSI tumors, which comprises CD8+ lymphocytes, CD4+ lymphocytes, NK cells,
and macrophages, is responsible for the increased secretion of various cytokines
such as TNF, granzyme, and perforin (Mlecnik et al. 2016).
Finally, Korehisa and colleagues investigated the role of programmed deathligand 1 (PD-L1) expression in MSI tumors; they assessed more than 400 CRC for
MSI status and then analyzed the expression of PD-L1 in cancer and stromal
compartment and tried to relate their data with survival and other histopathological
characteristics. They concluded that, compared to MSS tumors, MSI cases have a
higher expression of PD-L1 in both tumor and stromal cells; moreover, MSI tumors
with high PD-L1 expression had poorer differentiation and lymphatic and vascular
invasion compared to MSS cancers. For these reasons, MSI tumors may have a
potential benefit from PD-L1/PD1 inhibitors (Korehisa et al. 2018).
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However, if it’s true that MSI tumors have high TIL infiltrate, it’s not true that
TME characteristics depend solely on MMR status; in fact, the prognostic value of
immune infiltrate in CRC is statistically independent from MS status (Al-Badran
et al. 2021 ).
6 The Relationship Between TME and Chemotherapy in CRC
The relationship between TILs and neoadjuvant chemo-/radiotherapies in colorectal
cancer has been widely investigated. Many research groups have focused on
immunohistochemical analysis of lymphocytic subsets. For example, Teng and
coworkers analyzed pre- and posttreatment CD3+ and CD8+ lymphocytic infiltrates
of 136 rectal cancer patients that underwent neoadjuvant radio- and/or chemotherapy
and concluded that high pre-treatment levels of both CD3+ and CD8+ lymphocytes
were associated with high tumor regression grade (TRG ≥ 3) and favorable DFS and
OS (Teng et al. 2015). Yasuda and colleagues examined advanced rectal cancer
specimen that underwent neoadjuvant radiotherapy and analyzed the density of
CD4+ and CD8+ lymphocytes in preoperative samples. They noted that the number
of CD4+ and CD8+ cells correlated with TRG and histological grade; moreover,
CD8+ lymphocytes were an independent prognostic factor of complete response and
neoadjuvant therapy (Yasuda et al. 2011). Another study (Zhang et al. 2019)
compared the efficacy of neoadjuvant chemotherapy (NAC) and neoadjuvant
chemoradiotherapy (NACR) in relation to CD8+, CD4+, FOXP3+, and PD-L1+
TILs in more than 100 rectal cancer specimens. They noted that in NAC cases, high
levels of CD4+, CD8+, CTLA-4+, and PD-L1+ lymphocyt es were associated with
favorable response to therapy, while FOXP3+ cells were associated with poor
response to NAC. In NACR specimens, there was a higher infiltration of
CTLA-4+ TILs compared to NAC cases. Moreover, the levels of CD8 + TILs and
FOXP3 + TILs following NAC or NACR were independent prognostic factors.
Finally, Wang and colleagues (Wang et al. 2021a) evaluated the efficacy of chemotherapy alone or in combination with bevacizumab in metastatic colorectal cancers
in relation to CD3+ and CD8+ TILs in tumor core and invasive margin. Their results
highlighted the prognostic role of CD8+/CD3+ T-cell ratio for OS. In the chemotherapy+bevacizumab group, patients with CD8+ cell infiltrates at invasive margin
had longer OS and PFS, while in the chemotherapy group, patients with high CD8+/
CD3+ T-cell ratio had high response rate and those with high CD3+ cell count in
tumor core had longer OS. In conclusion, TIL density and composition have an
important role in predicting treatment efficacy and survival rates.
7 TME and Metastatic CRC
The most common cause of mortality in CRC patients is metastasis, being the liver
the main site of secondary lesions; 50 –60% of patients will develop liver metastasis
(Galindo-Pumariño et al. 2021), while the lung/thorax is the second most common
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site (Kamal et al. 2020). It is now clear that TME plays an important role in tumor
progression; according to the “seed and soil” hypothesis, tumor cells reach distant
sites where TME provides favorable conditions (Paget 1989). Regarding the liver,
for example, first of all the primary tumor prepares the distant niche by releasing
pro-inflammatory and pro-angiogenic factors, interleukins, and TGF-beta. All these
factors recruit various hepatic cells: Kupffer cells, hepatic stellate cells, and myeloidderived cells that produce growth factors. Subsequently, cancer cells migrate to
vessels through epithelial-mesenchymal transition promoted by CAFs. Circulating
tumor cells also activate cytotoxic liver cells and promote immune surveillance
evasion through CTLA-4 and PD-1 production (Galindo-Pumariño et al. 2021).
Kamal and coworkers reviewed the role of TME in CRC metastases (Kamal et al.
2020). They found that the lowest risk of progression was observed in tumor
subclones with low mutational burden, neoantigen depletion, and high CD3+
T-cell infiltration. The highest risk of progression instead was observed in
tumor subclones having immunogenic mutations. Moreover, immune-privileged
metastases that have low TIL level and lack immunoediting have greater risk to
recur.
Van den Eynde and colleagues (Van den Eynde et al. 2018) analyzed immune
infiltrate density of more than 200 patients with metastatic CRC. They performed
the Immunoscore® (see below) of primary lesions and metastases. Scientists found
that small metastases had low Immunoscore; moreover, high Immunoscore was
associated with a lower number of metastases. Finally, they concluded that the
degree of immune infiltration of CRC metastases was the most significant prognostic
indicator of tumor relapse, OS, and DFS.
8 TME Validated Scores
8.1 Tumor-Stroma Ratio
As stated above, H&E evaluation of immune cell infiltrates provides similar prognostic information compared to immunohistochemical studies, so investigators have
developed a reproduc ible score able to evaluate the abundance of immune cells
in TME: the tumor-stroma ratio. Tumor-stroma ratio (TSR) is defined as a histological feature that expresses the value of the stromal component that surrounds cancer
cells based on morphological evaluation of tissue sections on H&E slides (Souza da
Silva et al. 2021).
In their work, van Pelt and coworkers (van Pelt et al. 2018) illustrated the
evaluation procedure for TSR:
• The first step is to choose the H/E slide with the most invasive part of the tumor.
• Then select the area with the highest amount of stroma with 2.5× or 5× lens.
• Finally choose the area where both tumor cells and stromal cells are present at
10×.
• Estimate the amount of stroma tissue per 10% increment per image field.
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• Assign the calculated value to one of this two categories: stroma-high, in which
more than 50% of the area is occupied by stroma, or stroma-low, in which equal
or less than 50% of the area is occupied by stroma in the histological section.
TSR is considered an important clinical-pathological parameter and many studies
confirmed its prognostic value in CRC (Mesker et al. 2009; Huijbers et al. 2013; van
Pelt et al. 2016). In fact, Huijbers and coworkers found that stroma-high patients had
lower OS and DFS. Also Mesker and colleagues obtained similar results: they
concluded that stroma-high patients had poorer survival compared to stroma-low
cases.
In conclusion, TSR is a simple, reliable, and cost-effective prognostic parameter,
thus routinely usable by pathologists.
8.2 Immunoscore®
One of the first research groups working on TME scoring system was that of Galon
and coworkers. In the study published in 2006, they performed a combined genomic
and immunohistochemical study of lymphocyte infiltrates at both the center of the
tumor and invasive margin in more than 400 CRC cases; they used different IHC
markers to differentiate lymphocyte subpopulations (CD3, CD8, CD45RO) and
studied the expression level of genes related to inflammation and finally related
the results with prognostic data (Galon et al. 2006). After that, they demonstrated the
prognostic value of CD3+ cells in immune infiltrates of CRC and developed the
so-called Immunoscore®. This score was at first developed using CD45RO IHC to
mark memory T-cells and CD8 to mark cytotoxic T-lymphocytes in tumor center
and invasive margin. The score demonstrated a high prognostic value being predictive of OS DFS and DSS (Pagès et al. 2009). Subsequent studies of the same research
group (Mlecnik et al. 2011) further validated its prognostic value. In 2014, the group
modified the score (Galon et al. 2014): CD45RO has been replaced by CD3. They
also developed a digital image analysis of immune cells using a not publicly
available software (Hermitte 2016). Also the Immunoscore demonstrated a high
prognostic value and seemed to be superior to TNM parameters and MSI status
(Galon et al. 2016).
Afterward, other research groups have conducted similar studies trying to
validated the score and generally found a positive association with survival (Pagès
et al. 2018 ).
9 TME Analysis and Digital Pathology
In recent years, scientists have started comparing manual semiquantitative H&E or
IHC assessment of immune infiltrates to digital pathology technologies (Hendry
et al. 2017). For example, Vayrynen and colleagues (Väyrynen et al. 2012) assessed
immune cell density in CRC specimens via computer-assisted image analysis. They
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found that computer-based counting method provided more reproducible, rapid, and
accurate results than visual semiquantitative assessment. So they concluded that the
use of image analysis software is a valuable time-efficient alternative to manual cell
count.
In 2020, Nearchou and coworkers analyzed CD3+/CD8+ T-cells, CD68+/
CD163+ macrophages, and tumor budding in CRC specimens using automated
image analysis and machine learning approaches. They created a prognostic model
using CD68+/CD163+ cell ratio, lymphocytes within 50 μm to tumor buds, and
lymphocytic infiltration and identified a subpopulation of patients with better survival (Nearchou et al. 2020). In 2021, the same research group proposed two spatial
statistical methodologies for CD3+ and CD8+ lymphocytes and tumor budding and
applied these digital image analysis methods to 232 stage II CRC specimens. Thanks
to these new methods, they were able to develop new prognostic tools for CRC
patients (Nearchou et al. 2021). Another research group (Lin et al. 2021) used
artificial intelligence to provide an accurate profiling of spatial organization
characteristics of public H&E slides’ archive. They analyzed infiltrating lymphocyte
ratio (ILR) and infiltrating stroma ratio (ISR) and found that they had prognostic
value; in particular, they were associated with relapse-free survival (RFS).
All the aforementioned studies concluded that digital pathology is a valuable
tools aiding in patients’ prognostic stratification. However, digital image analysis
requires additional time and economicresources that need to be carefully considered.
Therefore, additional studies are needed to evaluate cost-benefit of these new
technologies.
10 TME as a Therapeutic Target
Nowadays, different types of therapies are directly acting on TME components.
For example, angiogenesis inhibition is considered a standard treatment for CRC
patients for some years now. Bevacizumab was the first VEGF inhibitor approved by
FDA, used alone or in combination with other agents, as a first or second line of
treatment. Subsequently, other agents were released: aflibercept, another VEGF
inhibitor, and ramucirumab, a monoclonal antibody against VEGFR2. All these
agents are used with a great clinical benefit from CRC patients (Fridman et al. 2020).
In the last few years, scientists also focused on CAFs as a possible therapeutic
target. Studies focused on various aspects: CAF reprogramming toward a normal
fibroblast phenotype or an antitumorigenic CAF phenotype acting on TGF-beta
signaling, blocking CAF signals such as chemokine CXCL12, and targeting other
ECM components in order to interfere with cancer cells communication (Sahai et al.
2020).
For example, among others, Yuan et al. studied the role of MyD88 signal
expressed by myofibroblasts in colitis-associated cancer (CAC) in mouse models
and found that MyD88 promoted M2 polarization of TAMs via osteopontin secretion and STAT3/PPAR-gamma pathway activation (Yuan et al. 2021). M2 TAMs
are known for their role in tumorigenesis. A few years earlier, Xie and coworkers
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studied MyD88 signaling pathway as a potential therapeutic target (Xie et al. 2015):
they developed a MyD88 inhibitor designed to interfere with its homodimerization
and tested it in a mouse model of CAC, obtaining encoura ging results.
Ma and colleagues studied the role of periostin in a CRC mouse model and found
that fibroblast periostin secretion, a protein involved in various inflammatory
diseases, contributes to tumor progression (Ma et al. 2020). For some years, periostin
has been studied by scientists as a possible target for inhibition or activation (Kudo
2019). Also STAT3 pathway has been investigated: Heichler and coworkers noted
that STAT3 activation and overexpression in CAFs tend to accelerate CRC
tumorigenesis in mice models (Heichler et al. 2020) and also cause chemoresistance.
For all these reasons, also STAT3 was taken into consideration as a possible
druggable target (Chalikonda et al. 2021).
Regarding immunotherapy, the possible role of PD-L1 inhibitors in CRC has
been widely studied. Studies conducted on MSS tumors with high infiltration by
T-lymphocytes demonstrated that this category of patients does not respond to
immune checkpoint inhibitors (Fridman et al. 2020). As stated above, MSI tumors
are characterized by a high tumor mutational burden (TMB) and a high neoantigen
load; therefore, they also have abundant intra- and peritumoral immune infiltrates;
moreover, the expression of PD-L1 is higher in these types of CRC, so patients may
potentially benefit from PD-L1 inhibitors, also considering that dMMR patients
benefit less from conventional chemotherapy. Immune checkpoint inhibitors block
checkpoint molecules such as PD-1 and CTLA-4 and activate T-cell anti-tumor
response.
For example, Le and colleagues evaluated the efficacy of PD-1 blockade with
anti-PD-1 antibody pembrolizumab in patients with dMMR advanced CRC and
observed that the immune-related objective response rate and immune-related progression-free survival rate were higher for mismatch repair-deficient colorectal
cancers compared to mismatch repair-proficient colorectal cancers (Le et al. 2015).
Another trial studied the clinical benefit of using nivolumab, an anti-PD-1 molecule,
and ipilimumab, an anti-CTLA4 monoclonal antibody, in combination in dMMR
CRC patients. Scientists concluded that the aforementioned combination provided
durable responses and clinical benefit for this category of patients (Overman et al.
2018). Moreover, in our institution, a study is ongoing for evaluating the impact of
TME, PD-1/PD-L pathway activation, and MSI on CRC prognosis.
Finally, in 2020, the US Food and Drug Administration (FDA) approved
pembrolizumab as first-line treatment of patients with unresectable or metastatic
MSI colorectal cancer.
Therapeutic molecules studied in MSI tumor cohorts in combination with checkpoint inhibitors are agents blocking colony-stimulating factor 1 receptor CCR2 and
CCR5 expressed by macrophages and myeloid-derived suppressor cells (MDSCs).
These molecules are able to induce macrophage repolarization and anti-tumor
immune response in M2 macrophages. Another strategy is to use alone or in
combination complement component 5a receptor (C5aR) blocking agents that regulate inflammatory responses and cancer development.
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Concerning MSS tumors, beta-catenin or PAX4 inhibitors are under studies; this
category of therapy could increase the immune infiltrate within the tumor and
consequently the anti-tumor immune response (Fridman et al. 2020). Scientists are
also exploring other possibilities like delivering T-cells directly to the tumor core
using chemokines such as CXCL9 and CXCL10 and antibodies or infuse effector
T-cells (Ganesh et al. 2019).
The most recent studies are focusing on the development of innovative strategies
such as oncolytic virus-based therapies, immunogenic chemo- and radiotherapies, or
cell-based therapies, like T-lymphocytes with chimeric antigen receptors or autologous TILs (Fridman et al. 2020).
11 Conclusion
The complex role of tumor microenvironment in colorectal neoplasm has long been
investigated. Most scientists agree that a brisk intra- and peritumoral immune cell
response is a positive prognostic factor; on the contrary, a low inflammatory
response is related to poor prognosis. Many studies investigated not only density
but also composition of CRC immune infiltrates and related these data to prognostic
indicators. Authors came to the conclusion that the influence of tumor microenvironment on patients’ prognosis is similar regardless of tumor cell types, except for
FOXP3+ lymphocytes and M2 macrophages. Other works focuse d on the best
method for immune cell assessment and compared semiquantitative methods based
on H&E slides’ evaluation and immunohistochemical assessment. Also in this case,
investigators obtained similar results regardless of the evaluation method used. In the
past few years, research groups focused on comparing manual H&E or immunohistochemical assessment methods with digital pathology. The implementation of
routine practice with digital image analysis software led to more precise immune
infiltrate counts and also to spatial organization evaluation of every single part of
TME. However, digital pathology has an economic cost, is time consuming, and
requires a specific training, so more studies are needed to carefully evaluate the
benefit-cost ratio of using new technologies in routine practice.
Also the possible role of TME component in CRC therapy has been widely
studied. Scientists focused mostly on immunotherapy, evaluating the benefitof
immune checkpoint inhibitors, and antiangiogenetic factors.
In conclusion, the literature available so far highlights how a dense and coordinated immune response is responsible for an effective anti-tumor activity of TME on
neoplastic progression. It is not a single cell type determining this but the choral of
the immune compartment. Nevertheless, there is a need for a standardized assessment method to incorporate in clinical practice to be place side by side with TNM
staging in order to better stratify patients’ prognosis and implementing therapeutic
strategies.
Acknowledgments None.
Compliance with Ethical Standards The authors declare that there is no conflict of interest.
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