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Page 8 of 24 Peyvandi et al. J Cancer Metastasis Treat 2019;5:44 I http://dx.doi.org/10.20517/2394-4722.2019.16

inflammatory cells, endothelial cells and osteoclasts should be considered as critical regulators of tumor
dormancy.

IMMUNOLOGICAL DORMANCY: ACTIVE CONTROL BY THE IMMUNE SYSTEM
The immune system can specifically recognize tumor cells through TAAs and initiate an anti-tumor
immune response through a multi-step process called immunoediting [164,165] : initially, the immune response
can effectively eliminate cancer cells and no metastases are formed (elimination phase). If a balance between
the tumor suppressive immune response and tumor evasion is achieved (equilibrium phase), the tumor mass
remains constant resulting in a state of immunological dormancy [166] . Tumor cells may eventually succeed
in evading the immune system through a combination of genetic evolution and exhaustion of the immune
system, and resuming growth to form macroscopic metastases (escape phase). Evasion involves multiple
mechanisms, including the down-regulation of TAAs or MHC molecules, secretion of immunosuppressive
cytokines, (e.g., IL-10 or TGF-b), recruitment of regulatory T cells (Treg), myeloid derived suppressor cells
(MDSC) or alternatively (M2) - polarized macrophages or by expressing immunosuppressive molecules
on the cell surface, such as PDL1 or B7 [167-169] , in multiple cancer types, including breast cancer [170] . The
occurrence and relevance of immunological dormancy in human cancer is difficult to grasp, as the absence
of biomarkers of dormancy makes it hard to investigate in patients. Also, there is paucity of clinically
relevant in vivo model for experimental studies [100] . Pommier et al. [171] have recently reported that patients
and mice with pancreatic ductal adenocarcinoma contained single quiescent DTCs lacking MHC-I
expression, which enabled them to escape immunity and establish latent metastases. Four cases of breast
cancer transmission to immunosuppressed transplant recipients from a single, clinically healthy donor have
been recently described [172] . The latency time to metastasis formation ranged from 16 months to 6 years, and
transmissions did not occur in a patient that discontinued immunosuppression. This unintentional situation
suggested that donor tissues harbored DTCs, which persisted in a latent state because of immune control,
while the immunosuppression of the recipient allowed the DTCs to resume growth [172] . Once cells have
escaped immunosurveillance it is unlikely that they can re-enter a second state of immunological dormancy,
because the mechanisms that eluded immunosurveillance are generally part of the genetic or epigenetic
tumor clonal evolution and therefore irreversible [59,91] .

The recent observation that immunosuppressive immune cells promote angiogenesis [157] , and that some
angiogenic factors, including VEGF, are immunosuppressive, established an important cross-talk between
these two systems [173-175] . They implicate that suppression of angiogenesis may stimulate the immune system
and that reversal of immunosuppression may inhibit angiogenesis in a bi-directional cross-talk. In support
of this notion, several trials have been performed to improve the anti-tumor immune response with anti-
angiogenic drugs [176] . Combination of anti-angiogenic agents with immunotherapy is currently being
considered as strategy to improve the response rates and duration of immunotherapy [177] . For example, VEGF
has been shown to suppress the immune-response by impinging on maturation of dendritic cells [178,179] .
Thus, inhibition of VEGF abrogates its immunosuppressive effect and improves the antitumor effect of
adoptive cellular immunotherapy [180] . Combining anti-VEGF therapies with check-point inhibitors (e.g.,
anti-PD-L1) has shown synergy and positive outcomes in phases I to III studies, particularly in patients with
high VEGF levels [177] . Using the 4T1 experimental model of TNBC we have demonstrated that inhibition
of tumor angiogenesis with the anti-VEGFR-2 antibody DC101, attenuated the inhibitory effect of MDSC
on T cell proliferation and decreased the frequency of Tregs in primary tumors and lung metastases [181] .
Combined angiopoietin-2 and VEGF inhibition was shown to promote superior vascular regression, tumor
necrosis, and enhanced the perivascular recruitment of cytotoxic T lymphocytes, as compared to the single
agents in multiple cancer models. Addition of a PD-1 blocker unleashed the cytotoxic activity resulting
in improved tumor control [182,183] . These findings support the rationale for combining anti-angiogenic
therapy with immune checkpoints inhibitors in cancer therapy, including in breast cancer. In addition to
immunosuppressive angiogenic molecules, endothelial cells themselves also play a direct role in modulating