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Another promising strategy in targeting cancers in vivo cells. This immune checkpoint inhibitor will help the
is adoptive transfer of chimeric antigen receptor (CAR) body’s immune system fight against cancer cells. [74]
engineered T cells, which can specifically target any
TAAs or cancer stromal antigens with high binding In addition to previously reported suppressor molecules,
affinity. Preclinical models have been developed as a CD200 (OX-2) is another immunosuppressive factor that
[75]
proof of concept that CARs could also be used to target may have an important role in CSC’s immunoevasion.
CSCs. Deng et al., for instance, demonstrated CD200 is co-expressed with CSC markers such as
[57]
[58]
that CAR T cell therapy could inhibit tumor growth of CD133 glioblastoma, colon and melanoma CSCs,
+
highly metastatic prostate cancer that expresses low CD44 /CD24 in breast CSCs and CD44 prostate
+
-
+
levels of EpCAM. Other CSC-targeting adoptive T cell CSCs. [76,77] Upregulation of CD200 negatively correlates
therapies include CAR T cells which bind to a CSC- with the levels of Th1 cytokines required for effective
specific N-glycosylation-dependent epitope of CD133, T cell activation, such as IL-2 and IFNγ. [78-80] Shifting
[59]
high-molecular weight melanoma associated antigen or of Th1 to Th2 cytokine production is observed in the
chondroitin sulfate proteoglycan 4-specific CAR T cells progression of many cancer types and is a characteristic
that were reported to specifically eliminate melanoma of the tumor microenvironment, especially in carcinomas
with a CSC phenotype, [60,61] and epidermal growth factor with poor prognosis. [78]
receptor variant III (EGFRvIII) specific CAR T cells
which target glioma SCs. [62] TARGETING THE TUMOR
MICROENVIRONMENT
Cells in the tumor microenvironment was also found
to express several negative immune regulators such as The tumor microenvironment of CSCs has three
programmed cell death 1(PD-1) and its ligand (PD-L1), major characteristics: (1) chronic inflammation and
cytotoxic T lymphocyte associated 4 (CTLA-4), and secretion of inflammatory cytokines, (2) hypoxia,
[82]
[81]
transforming growth factor β (TGF-β). Engagement and (3) perivascular niches that regulate the capacity
[63]
of CTLA-4 attenuates activation of downstream of proliferation and differentiation. Inflammatory
[83]
inflammatory cytokines, which contribute to T cell cytokines such as IL-1β, IL-6 and IL-8 activate the Stat3/
antitumor immunity, such as IL-2 and IFN-γ. [64,65] In NF-κB pathways in tumor and stromal cells to further
T s, the engagement of CTLA-4 is required for immune secrete cytokines in a positive feedback loop that prompts
reg
suppression. Antibodies blocking CTLA-4 engagement CSC self-renewal, angiogenesis, and metastasis. [81,84]
[66]
were developed and tested for their cancer therapeutic Moreover, the CSC population along with other cells
potential. Wu et al. showed that CTLA-4 monoclonal which coevolved in the tumor microenvironment are near
[67]
[68]
antibody (mAb) was able to inhibit early stages of blood vessels that form a niche characterized by severe
tumor growth in a murine mesothelioma model and hypoxia and increased angiogenesis. [82,83] These aspects
improved tumor infiltration of CD8 and CD4 T cells. of the tumor microenvironment have been explored as
+
+
In human patients with advanced melanoma, the CTLA- possible pharmaceutical targets of CSCs.
4 mAbs ipilimumab and tremelimumab prolonged T
cell activation. However, only ipilimumab demonstrated Recent studies have demonstrated decreased tumor
improved survival in phase III study of patients with growth after blocking IL-6 and/or IL-8 cytokine
previously treated melanoma and gained FDA approval signaling. [85,86] One of the pharmaceutical molecules
for treatment of metastatic melanoma in 2011. Future tested was repertaxin, a non-competitive inhibitor of
[69]
applications of mAb CTLA-4 will most likely come in the IL-8 and CXCR1 signaling, which decreased tumor size
form of combination therapy to modulate the host immune and increased efficacy of chemotherapy. However, the
[87]
system in a more effective synergistic fashion . [67,68,70,71] effects of blocking single cytokines is limited as both IL-6
and IL-8 are critical for xenograft tumor growth and the
The second T cell regulatory pathway is the PD1/PD- combined expression of these genes correlates with poor
L1 axis, which inhibits lymphocyte activation. PD-L1 prognosis in patients with breast cancer. Therefore, co-
or B7 homolog 1 (B7-H1) is expressed in many tumors inhibition of both IL-6 and IL-8 was suggested to be a
including melanoma and cancers of the lung, colon, more advantageous method to induce substantial effects
ovarian, liver and breast. [63,72] PD1/PD-L1 binding triggers on tumor growth. [88]
apoptosis of B and T cells in the tumor microenvironment.
In tumors with upregulated PD-L1 expression, there is Tumor hypoxia is another intriguing method for attacking
decreased T cell infiltration, activation, and expansion, CSC niches. Hypoxia activates the hypoxia inducible
effectively shielding CSCs against the host’s immune factor (HIF) pathway and upregulates HIF-1α, which
response. [63,72,73] Most recently, the new immunotherapy mediates multiple biological effects of hypoxia in
drug which has been approved by FDA in May 2016. tissues and increases resistance against chemotherapy
Tecentriq is a monoclonal antibody that targets the PD-1/ and radiation. Several small molecule inhibitors of
[89]
PD-L1 pathway by directly binding with a PD-L1 protein the HIF pathway have been pursued in clinical trials,
expressed on tumor cells and tumor-infiltrating immune although only a few of them were successful. Bortezomib
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ July 8, 2016 ¦ 237