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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 3 of 14

inflammatory response is activated promoting angiogenesis and tumor cells proliferation. Later, adaptive
immune response is triggered by interaction and recognition between non-self-antigens and peptides
[15]
presented by the major histocompatibility complexes (MHC) of APCs and T cells .
Immune system cells play different roles during tumor immune response. CD4+ cells sustain inflammatory
response by secreting a variety of cytokines such as interferon γ, tumor necrosis factor α, interleukin-2
(IL-2), and IL-17. CD4+ cell activation promotes proliferation and function of a specific subgroup of
CD8+ cells called cytotoxic T lymphocytes, that are capable of direct lysis of tumor cells. CD8+ cells
can also secrete cytokines causing cytotoxic response. NK cells are involved in antibody-dependent cell-
mediated cytotoxicity and natural cytolytic activity against tumor cells. Macrophages destroy cancer cells
through phagocytosis and release matrix-degrading substances (metalloproteinases and cysteine cathepsin
proteases). Consequently, high levels of metalloproteinase represent an important factor to predict CRC
[16]
prognosis and metastasis .

Part of the cells described above make up tumor-infiltrating lymphocytes (TILs) that showed to have a
[17]
prognostic role in cancer treatment and appeared often to be associated with better clinical outcomes .

Mesenchymal stem cells (MSC) are non-hematopoietic stromal cells with proliferative potential,
immunosuppressive properties, and ability to differentiate into several cell types. Their immunosuppressive
function is releasing of proinflammatory factors, inhibiting lymphocyte proliferation and DCs maturation,
promoting the production of macrophages, and regulating T cells (Treg). MSC are also involved in tumor
initiation, angiogenesis, resistance to chemotherapy, invasion and metastatic process.

Criteria such as composition, density and location of TILs have shown to correlate with different prognosis
indicators. Notably, in CRC the number and location of cytotoxic and memory T lymphocytes can predict
[19]
[18]
tumor recurrence and prognosis in early-stage CRC . Mlecnik et al. observed that CRC presenting low
CD8+ cytotoxic T-lymphocyte (CTL) infiltration were associated with higher tumor growth and metastatic
spread. Conversely, patients whose tumor showed high density CD8+ CTL were more likely to have early-
stage exordium. Moreover, among patients relapsed, CD8+ CTL infiltrate appeared to be low independently
to TNM stage. These findings support the hypothesis that lymphocyte infiltration represents a strong and
independent prognostic factor in CRC.

Tumors cells are well known to develop strategies of immune escape. Indeed, they may show genetic
alterations that enhance the expression of mesenchimal transition or immunosuppressive genes along
with chemokines responsible for immune suppressive cells recruitment, conferring to cancer cells innate
resistance to anti-programmed cell death-1 (PD-1) drugs. Different mutations might be responsible for
resistance acquired after an initial benefit out of immunotherapy; during clonal expansion a resistant clone
develops high proliferation potential and drives resistance advance.

For example, loss-of-function mutations in Janus Kinases 1/2 (JAK 1/2) might be responsible both for
primary and adaptive resistance to immunotherapy. These inactivating mutations affect interferon gamma
signaling rendering cancer cells unable to respond to interferon gamma by expressing programmed cell
death ligand-1 (PDL-1) and other interferon-stimulated genes, and patients with such tumors became
unlikely to respond to PD-1 blockade therapy. This mechanism has already been described in melanoma
[20]
patients. Zaretsky et al. analyzed biopsy samples from paired baseline and relapsing lesions in four
metastatic melanoma patients who experienced disease progression after an initial objective tumor
regression and found resistance-associated loss-of-function mutations in the genes encoding JAK1 or JAK2,
[21]
concurrent with deletion of the wild-type allele. Shin et al. described the case of one patient with dMMR
colon cancer who did not respond to anti-PD-1 therapy despite a high mutational load, thus identifying
JAK1/2 mutations also as potential mediators of primary resistance to PD-1 blockade.