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Page 2 of 14 Bittoni et al. J Cancer Metastasis Treat 2018;4:55 I http://dx.doi.org/10.20517/2394-4722.2018.37

metastasis, and type of treatment given. Tumor genetic mutations gained a pivotal role as the prognostic
[1]
factor. To date, the median overall survival (OS) for patients with metastatic CRC is about 30 months . In
[2]
2015, 70% of new cases underwent potentially curative resection thanks to screening programs .
In the past years, research on CRC has shown an emerging interest in genomic and immunologic
fields. The clinical heterogeneity that occurs during the pathogenesis of CRC is driven by chromosomal
[3]
alterations and defective function of DNA mismatch repair (MMR) systems . In particular, about 15%-20%
of CRC show deficient mismatch repair (dMMR) systems, while chromosomal instability with functioning
[4]
DNA MMR, a status defined as microsatellite stable (pMMR), is found in 80%-85% of CRC .

Microsatellites are defined as areas within the DNA sequence where a single nucleotide (mononucleotide)
or units of two or more nucleotides are repeated in genome. They are usually located in the introns of
genes and the number of repeats contained in every microsatellite is usually preserved in every single
[5]
cell of the body . Microsatellite instability (MSI) is defined as a clonal change in the number of repeated
DNA nucleotide units in microsatellites and it arises in tumors with dMMR due to the inactivation of one
of the four MMR genes: MSH2, MLH1, MSH6, and PMS2. Considering that a minority of tumors display
instability in fewer than 20% of the markers studied, a classification has been proposed that identifies MSI-
low (with just one unstable marker in out of the five-marker Bethesda panel) and MSI-high (with two or
[6]
more unstable marker) .

Clinical and biologicals differences between dMMR and pMMR are well established. Specifically, dMMR
causes genetic instability (aneuploidy, allelic losses, amplifications, translocations, and chromosomal gains)
[7,8]
that influences the expression of genes leading to CRC carcinogenesis . On the other hand, dMMR CRCs
have shown better prognosis compared to pMMR tumors [9-11] . The increased mutation rate of dMMR
tumors triggers an increased production of potentially immunogenic peptides or epitopes establishing a
rationale for immunotherapy in this CRC subtype while few data regarding immunotherapy efficacy in
pMMR tumors are available in literature . In this review we analyzed the role of immunotherapy and
[12]
target agents in dMMR and pMMR.

Role of the immune system in CRC
Conventionally, clinical and pathological features, along with tumor characteristics, are known to define
cancer aggressiveness. Nevertheless, in the past years, tumor microenvironment (TME) has shown to play
an important role in tumor growth and metastatic potential. TME is composed of epithelial cells, blood
and lymphatic vessels, stromal cells, and infiltrating immune cells, including T lymphocytes, B cells,
natural killer (NK) cells, dendritic cells (DCs), macrophages, and granulocytes. Each tumor displays a
specific composition of TME and CRC shows a high degree of immune cell infiltration and high presence
[13]
of mesenchymal stromal cells .
Studies in this field highlighted that different constituents of TME may influence tumor proliferation,
infiltration and metastatic spread in different ways. Cancer growth or inhibition represents the result of the
interplay between tumor cells and TME. Immune system has been demonstrated to be a key-mechanism of
tumor regulation.

Immune system recruits, in cancer surveillance, the coordinated and balanced activation of both innate
immune cells [such as macrophages, neutrophils, myeloid derived suppressor cells (MDSC), mast
cells, eosinophils, and antigen-presenting cells (APCs)] and adaptive immune cells (NK cells, T and B
[14]
lymphocytes cells) .
At first, innate immune system is recruited by abnormal cells without specific antigen recognition and