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Page 2 of 17 Spallanzani et al. J Cancer Metastasis Treat 2018;4:28 I http://dx.doi.org/10.20517/2394-4722.2018.31

Nevertheless, about 50% of patients develops metastases during the course of their disease. In these
patients, chemotherapy (fluoropyrimidines, oxaliplatin and irinotecan) with biological agent [anti-vascular
endothelial growth factor (anti-VEGF), anti-epithelial growth factor receptor (anti-EGFR) and multikinase
inhibitor such as regorafenib] remains the standard of care, with median overall survival approaching
[4]
30 months .

The molecular characterization of colorectal cancer has led to the identification of favorable and unfavorable
[5]
immunological features linked to clinical outcome .

Currently, CRC is classified into four consensus molecular subtypes (CMS), with unique clonal, stromal and
[6]
immune dependences .

The immune system has a substantial effect on cancer, especially as a suppressor of tumour initiation and
progression. Additionally, it influences the response to immunotherapeutic and conventional treatment
options (e.g., chemotherapy, radiotherapy and targeted therapies). However, the tumor can establish
several mechanisms to escape immune surveillance. Therefore, different strategies may be pursued to
restore the immune response against cancer cells, both as an active immunotherapy (cytokines, immune
checkpoint inhibitors, co-stimulatory pathways and cancer vaccines) and as a passive immunotherapy
[7]
(adoptive cellular therapy and monoclonal antibodies) approach . FDA has recently approved checkpoint
inhibitors (nivolumab and pembrolizumab), for the treatment of patients with microsatellite instability
(MSI) metastatic CRC. However, the most unsolved problem is the lack of efficacy of these antibodies in
microsatellites stable (MSS) tumours, which represent the majority of CRC.

In this review we summarize the biological bases and the recent clinical evidences related to the use of
immunotherapy in metastatic colorectal cancer (mCRC) to suggest different treatment strategies according
to different CMS, transcriptomic pathways and stroma-immune microenvironment.

RATIONALE FOR IMMUNOTHERAPY IN CRC
The immune system has a major role in cancer: immune cells can act both as suppressors of tumor initiation
and progression and as promoters of proliferation, infiltration and metastasis.

[8]
[9]
In 1970 Burnet proposed the concept of immune-surveillance, that was updated by Dunn et al. and
[10]
Schreiber et al. with the identification of the process of immunoediting. This process consists of three
well-defined phases: elimination, equilibrium and escape. The elimination phase refers to active surveillance,
and includes innate and adaptive immune responses to tumour cells. First of all, cells of the innate immune
system (NK cells, NK T cells, macrophages and dendritic cells) recognize the presence of a growing
tumor after its stromal remodeling, a local tissue damage and the release of inflammatory signals, which
recruit these cells to the tumor site. They produce IFN-gamma and IL-12, and destroy most of cancer
cells, even if some of them survive and reach the “equilibrium” phase. Therefore, in the elimination phase,
the release of IFN-gamma and production of chemokines as CXCL10, CXCL9 and CXCL11 determine
the inhibition of angiogenesis. Meanwhile dendritic cells migrate into the draining lymph nodes and
promote the differentiation of Th1 cells into cytotoxic CD8+ T cells. In the equilibrium phase tumor cells
that have escaped the elimination phase and have a non-immunogenic phenotype are selected for growth.
Progressively these cells become unstable and acquire various mutations, so they will be able to grow despite
immune attack and reach the escape phase. In this third phase, tumor cells continue to grow and may lead
to malignancies.

[11]
In this process we can identify three main characters :
1. Tumour cells have several mechanisms that block the activity of effector antitumor CD4+ and