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Bittoni et al. J Cancer Metastasis Treat 2018;4:55 I http://dx.doi.org/10.20517/2394-4722.2018.37 Page 5 of 14

favorable prognosis, while CMS4 subgroup have high density of endothelial, myeloid cells and fibroblasts
with higher production chemokines and cytokines that support tumor-associated inflammation, stromal
invasion and, angiogenesis, resulting in worse prognosis. These findings stress the role of TME functional
orientation beyond TILs composition.

Regarding the others subgroups, CMS2 and CMS3 that occur approximately in 50% of CRC, have low
immune and inflammatory infiltration and, intermediate prognosis [27,28] .

Also tumor genetic signature has a strong prognostic value. It is reported that stromal composition might
strongly affect tumor transcriptional profile hiding tumor cell intrinsic transcriptional traits, especially in
those tumors whose gene expression is largely sustained by stromal cells. Using patient-derived xenografts,
[29]
Isella et al. developed an approach to unmask CRC cell specific transcriptional features. Based on these
findings, five CRC intrinsic subtypes (CRIS) were identified. CRIS-A includes MSI-like, BRAF- or KRAS-
mutated tumors with mucinous expression and glycolytic, pro-inflammatory features. CRIS-B encompasses
poorly differentiated tumors characterized by high TGF-β driven activation and stressed epithelial-
mesenchymal transition traits. CRIS-C groups KRAS wild-type tumor with chromosomal instability
expressing elevated levels of epidermal growth factor receptor (EGFR). CRIS-D clusters stem phenotype
tumors with active Wnt pathway and insulin-like growth factor-2 amplification and overexpression. In
CRIS-E subtype Wnt signaling is again observed but it is associated with Paneth-like phenotype and
mutations in TP53.

Many of these traits differ from those reported in other transcriptional classification, confirming the strong
influence of stromal contexture. CRIS grouping may be applied both to primary and metastatic CRC with
low overlap on previous transcriptional classifications. Interestingly, CRIS subtypes were demonstrated to
[29]
have new prognostic and predictive potentials .

Immunotherapy in MSI CRCs
In the past years, research on immunology and molecular biology fields has clarified the role of the
immune system in cancer growing and metastatic potential of tumors. Interestingly, MSI tumors show a
marked predisposition to express a wide variety of neoantigens reflecting a significantly high mutational
burden [20 fold higher compared to microsatellite stable (MSS)], due to dMMR. The load of neoantigens
and the pronounced expression of T-cell recruiting chemokines cooperate to sustain an active immune
TME characterized by diffuse immune infiltrate. This explains why CMS1 subtype is recognized as highly
immunogenic. This consideration builds up a strong rationale for the use of immunotherapy in MSI
[30]
CRC. Furthermore, Llosa et al. proposed an interaction between tumor gene expression and immune
microenvironment in CRC. Not only did they report an association between MSI tumors and Th1/CTL
rich infiltrate, but they also observed that MSI tumors showed enhanced expression of several immune
checkpoints, as to balance such an active immune microenvironment. This might explain both the natural
development and growth of tumors that should be easily eliminated by the immune system and the
possible efficacy of checkpoint inhibitors in this setting.

Immune system defends our bodies from non-self antigens activating immune response. However, it
is pivotal that immune defenses arise at the appropriate time and are limited when they are no more
requested in order to prevent chronical inflammation and autoimmune disease. A variety of co-inhibitory
checkpoints are engaged to balance activation signals.

One of the most important immune checkpoints is represented by PD-1 and PDL-1. PD-1 is expressed on
activated T-cells while PDL-1 is usually expressed on APCs’ surface and their interaction mediates a co-
inhibitory stimulus that limits excessive immune responses in peripheral tissues ensuring the maintenance