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

Another mechanism that has been accounted for acquired resistance to immunotherapy in melanoma is
inactivation of beta-2-microglobulin (B2M), a fundamental component of the antigen-presenting MHC I.
[22]
Le et al. (which included in their study 40 patients with CRC and 46 patients with 11 other histologies)
identified mutations of the B2M gene in four of five tumors with acquired resistance to anti-PD-1 therapy.
However, no B2M mutations were identified in primarily resistant tumors. The recognition that the above-
mentioned mutations would lead to primary or acquired resistance to PD-1 therapy might be useful to
building oncogenic sequencing panels used to select patients for treatments.

The tight interaction between tumor and immune system has driven to the hypothesis of cancer
immunoediting. This concept reinvented tumor immunosurveillance taking into account the dual role
played by immune responses as host-protective and tumor-promoting. According to immunoediting cancer
growth is structured in three different phases: elimination, equilibrium and escape. In the elimination
phase immune system engages both innate and adaptive response to eliminate developing tumors before
they become clinically evident. If this phase is satisfactorily fulfilled and the tumor results fully eradicated,
the whole process might be considered completed. However if a single cancer cell variant escapes the
elimination phase it proceeds to the equilibrium phase. During the second phase clonal growth of selected
cell variant is prevented by immune system, but those cells still survive in a state of dormancy. Notably,
adaptive responses are engaged in the equilibrium phase which is also the time of cancer immunoediting.
Also equilibrium might be the end of the entire process whether the immune system keeps under control
the “survivor cells” for the lifetime of the host. Nevertheless, the continuous immune pressure on tumor
cells may lead them to enter the escape phase. In this third phase tumor variants elude immune system
with different mechanisms and they outgrow to clinically apparent cancer [23,24] .

CMS 1-4 and immune classification
As previously reported CRC clinical pathological characteristics and tumor TMN stage largely affect CRC
prognosis and drive treatment choices along with mutation in RAS and BRAF genes. Nevertheless, patients
sharing same TNM stage and therapies end up with different outcomes suggesting that key factors are still
missing to our knowledge and approach. To attempt a more inclusive classification, different criteria were
[25]
proposed that take into account also composition, density and location of tumor immune infiltrate . An
example of these efforts is the “Immunoscore” for tumor immune classification promoted by Galon’s group.
[26]
This immune-based classification demonstrated to have a good and independent prognostic value .

Furthermore, an international consortium of experts has introduced a gene expression and immune -based
classification system: the “consensus molecular subtypes” of CRC, providing new prognostic and predictive
[27]
tools . CRC is classified in four CMS and a fifth unclassified group. CMS1 group, also called MSI-like,
includes tumors with instability of microsatellite due to mutations in MMR proteins and BRAF oncogene
mutations. This subtype is also characterized by a diffuse immune infiltrate, composed of T helper
cells and cytotoxic T cells. CMS2 subtype, also called canonical, encopasses tumors with chromosomal
instability and upregulation of c-MYC and Wnt proto-oncogene pathways. CMS3 subtype, also known
as metabolic, encompasses tumors with mutated KRAS and tumors presenting metabolic dysregulation.
CMS4, also known as mesenchymal subtypes includes tumors with mesenchymal phenotype, high
expression of mesenchymal genes, stromal infiltration, angiogenesis and transforming growth factor beta
(TGF-β) activation. The four subtypes have different frequency, immunogenic characteristics and prognosis
with CMS1 and CMS4 recognized as the most immunogenic subtypes, both characterized by high levels of
immune infiltration [13,17] .

[28]
Becht et al. in a retrospective analyses demonstrated that high levels of TILs reported in CMS1 and
CMS4 have different functional characteristics leading to different prognoses. Although both subtypes
have high CD8+ T lymphocytes and macrophage infiltrate, CMS1 patients show a Th1 polarization, with