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Page 10 of 24 Peyvandi et al. J Cancer Metastasis Treat 2019;5:44 I http://dx.doi.org/10.20517/2394-4722.2019.16

acute lymphoblastic leukemia, colorectal, lung, liver and breast cancers [190-196] . In addition, chemotherapy
pre-exposed DTC may develop mechanisms of chemoresistance and become less responsive to subsequent
chemotherapies, as is often observed at relapse in patients. CSCs have been shown to be chemo-resistant and
to be responsible for post-therapy relapses [197] . Chemotherapy causes enrichment of CSCs thereby facilitating
recurrences and resistance to further chemotherapies in multiple cancers including glioma, ovarian, liver,
colon, breast cancers [197] . Resistance involves multiple mechanisms, such as activation of signaling pathways
prominent in stem cells (e.g., WNT, NOTCH, HEDGEHOG) [198-200] , but also pathways that are frequently
mutated and activated in cancer, in particular the EGFR-HER2/PI3K/PTEN/Akt/mTORC pathway [198,200,201] .
CSC are often enriched at sites of chronic hypoxia leading to the activation of the HIF pathway [200,202] .
Interestingly, HIF activation leads to the initiation of protective pathways, including WNT and NOTCH,
and genes of the ATP-binding cassette (ABC) drug transporter family members, such as MDR1, MRP1
and ABCG2 which are responsible for the efflux of cytotoxic drugs from the cells [203-208] . Additional, HIF-
independent mechanisms have been reported [209] . In short, the mechanisms behind the long-term beneficial
effects of adjuvant chemotherapy remain in part elusive and cannot be fully explained by the direct cytotoxic
activity of chemotherapy as dormant/CSC that are mostly responsible for late relapses that are highly
resistant to chemotherapy.

IMMUNE RESPONSE AND CHEMOTHERAPY IN BREAST CANCER
Cumulating evidence indicates that tumor infiltrating lymphocytes (TILs) play an active role in controlling
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progression and clinical outcome in breast cancer, particularly in highly proliferative TNBC and HER2
cancers [210-212] , and in conjunction with chemotherapy [213,214] . This is particularly relevant to TNBC, as these
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cancers present the richest presence of TILs, most notably CD8 T lymphocytes, and tertiary lymphoid
structures [211,215,216] . Increased numbers of infiltrating TIL in TNBC, are associated with an improved
pathological complete response to chemotherapy [217] , decreased rates of recurrences and improved
survival [210,216,218] . Evaluation of TILs in breast cancer has been recommended as an immunological
biomarker with prognostic and potentially predictive values, mainly in TNBC and HER2-amplified breast
cancers [219] . In TNBC, expression of antigen presenting MHC class II pathway molecules is associated with
a better outcome, consistent with the hypothesis that a functional antigen presentation pathway may trigger
a protective antitumor immune response in response to chemotherapy [220] . Ladoire et al. [221] demonstrated
that pathological complete response to neoadjuvant chemotherapy of breast carcinoma resulted in the
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disappearance of tumor-infiltrating FOXP3 regulatory T cells and the increase in tumor infiltrating
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cytotoxic TiA1 and granzyme B T cells, consistent with the induction of an antitumor immune response
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by chemotherapy. While the association between lymphocytic infiltrates, and improved outcome after
chemotherapy appears to be strongest in TNBC and HER2 breast cancer subtypes, the association with
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luminal tumors is less clear, and may be limited by the reduced immune infiltration or by the greater tumor
heterogeneity of these tumors [222] . Several recent experimental studies have shown that chemotherapy can
induce a therapeutic anti-tumor immune response. For example, Ma et al. [223,224] , reported that anthracycline-
based chemotherapy induces the release of ATP by dying breast cancer cells, which promotes the
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high
recruitment and differentiation of CD11c CD11b Ly6C antigen presenting cells. Depletion or preventing
tumor infiltration by these cells abolished the anti-tumor immune responses elicited by anthracyclines [223,224] .
Besides these desired immunological effects, chemotherapy can also induce unwanted, immune-mediated
tumor-promoting effects. For example, increased expression of TNFa in the breast tumor microenvironment
due to chemotherapy, induces CXCL1/2 expression via NF-κB activation in breast cancer cells and
initiates a paracrine loop involving myeloid cell-derived S100A8/9 to enhance cancer cell survival and
chemo-resistance. Inhibition of CXCR2 blunt this TNFa-induced response and augments the efficacy of
chemotherapy, particularly against breast cancer metastasis [225] .