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Page 8 of 15 Abe et al. J Cancer Metastasis Treat 2020;6:51 I http://dx.doi.org/10.20517/2394-4722.2020.117

could be a therapeutic target in this sarcoma in addition to osteosarcoma [41,45.46,50] , rhabdomyosarcoma [62,64] ,
[79]
synovial sarcoma, and fibrosarcoma , as discussed above.

GSK3b and upfront therapies in bone and soft tissue sarcomas
Immunotherapy
Immunotherapy has recently attracted considerable attention for the treatment of many cancer types [88,89] . It
has also emerged as a possible upfront therapy for bone and soft tissue sarcomas [17,90-92] . Currently available
cancer immunotherapies are based on innate immune reactions represented by natural killer T (NKT)-
+
cells against cancer cells, adoptive anti-tumor immunity exerted by CD8 memory T cells and genetically
engineered chimeric antigen receptor (CAR)-T cells, vaccination with tumor-specific antigens, and finally
on the blockade of immune checkpoints with therapeutic antibodies to programmed cell death 1 (PD-1),
programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) [88,89] .
Various regimens consisting of many of these immunotherapeutic cells and agents either alone or in
combination with chemotherapy, radiation or other targeted agents have been evaluated in many early
phase (I or II) clinical trials. Unfortunately, most have so far resulted in disappointing outcomes [17,90-92] .

As reviewed recently by ourselves and others [30,32] , inhibition of GSK3b in normal peripheral NKT cells
facilitates their maturation and enhances their cytocidal effects against acute myeloid leukemia cells [93,94] .
+
In adoptive tumor immunity, CD8 memory T-cells differentiate into pluripotent memory stem T-cells that
[95]
are capable of self-renewal and have anti-tumor properties via activation of the Wnt/b-catenin pathway .
+
Consistently, GSK3b inhibition enhances the cytotoxic effect of CD8 memory stem T-cells against gastric
[96]
+
cancer cells through the induction of effector T-cell-derived Fas-ligand . Similar to CD8 memory T-cells,
inhibition of GSK3b in mouse glioblastoma-specific CAR-T cells increased their survival, proliferation,
[97]
and generation of memory phenotype, thereby enhancing their cytotoxic capacity . During the blockade
+
of immune checkpoints between tumor cells and CD8 memory T-cells, inactivation of GSK3b suppresses
PD-1 expression via upregulation of the transcription factor Tbx21, thereby enhancing CD8 cytotoxic
+
T-cell responses [98,99] . Moreover, GSK3b inhibition reverses the blockade of CD28 by CTLA-4 [100] that is
+
required to rescue exhausted CD8 T-cells [101] . These preliminary findings suggest broader roles for GSK3b
within the cancer immunosuppressive environment by negatively regulating innate and adoptive anti-
tumor immune reactions and by sustaining the immune checkpoints mediated by the PD-1/PD-L1 axis and
by CTLA-4 [102] . Consequently, these early studies hold considerable promise for targeting GSK3b during
immunotherapy for various cancer types [102] including bone and soft tissue sarcomas [Figure 2].

MSC therapy in bone sarcomas
MSCs are a rare population of non-hematopoietic stromal (stem) cells in the bone marrow and other
connective tissues such as adipose tissue. They are capable of self-renewal and of undergoing differentiation
into the specific mesenchymal cell types. MSCs have attracted widespread interest in sarcoma research
and management as a plausible origin of tumorigenesis and as a component of the tumor-promoting
microenvironment [103-105] . Paradoxically, MSCs could also be potential cellular weapons in therapeutic
applications [106,107] . Studies have shown that MSCs contribute to osteosarcoma progression through their
ability to home into the tumor and induce neovascularization and elicit an immunosuppressive tumor
environment, thereby sustaining tumor cell survival and proliferation [105,108] . Conversely, other studies
reported that MSCs suppress proliferation and induce apoptosis in tumor cells while altering the properties
of stromal cells to induce anti-inflammatory effects, inhibit tumor angiogenesis, and ultimately prevent
metastasis [107,108] .

Based on the tumor site tropism of MSCs, several recent laboratory studies have genetically engineered
MSCs to function as vehicles for the delivery of various anti-tumor agents. These agents include interferons
(e.g., IFN-α), interleukins (e.g., IL-12), oncolytic viruses (e.g., coxsackie and adenovirus), tumor necrosis
factor (TNF)-α, TNF-related apoptosis-inducing ligand (TRAIL), therapeutic antibodies, and enzyme/