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Page 2 of 19 Mondal et al. Neuroimmunol Neuroinflammation 2018;5:34 I http://dx.doi.org/10.20517/2347-8659.2018.13

Conclusion: Collectively, the above experimental evidence hints towards gliomagenic maneuver of receptor expression of
HSCs to derange the systemic immunity and T11TS mediated manipulation towards revival/rejuvenation of the same.

Keywords: Glioma, immunosupreesion, T11TS, immunotherapy, hematopoietic stem cells, immunophenotyping,
immunomodulation

INTRODUCTION
Systemic depression of cellular immunity and subsequent global immune suppression is the classical
poor prognostic fact of gliomagenesis . Debilitating gliomas evade the host immune surveillance either
[1]
by adopting immune-editing strategies such as impairment of antigen presenting machinery , activation
[2]
of negative co-stimulator signals for example cytotoxic T-lymphocyte-associated protein 4 (CTLA4), B7
homolog 1/programmed death 1 (PD1) and Programmed death-ligand 1 (PDL1) and recruitment of pro-
[3-5]
apoptotic pathway [e.g., Fas receptor, Fas ligand (FasL)] , expansion of regulatory T cell population and
[6]
[7]
down regulation or absence of tumor specific antigen or by secreting cytokines such as interleukin 10 (IL-10),
[8]
interleukin 6 (IL-6), transforming growth factor beta 1 (TGF-β), prostaglandin E2 (PGE2), and various
gangliosides which have been implicated for their direct immune suppressive role to diminish the antitumor
immune response during glioma progression [9-11] .
Interestingly, gliomagenic generation of potent immune suppressors in addition acts as intense inhibitory regulators
of hematopoiesis by modulating the function of bone marrow hematopoietic stem cells (BMHSCs) [12,13] . TGF-β, a key
negative regulator of hematopoiesis not only suppresses in vitro proliferation of both progenitors and mature
stem cells but also induces quiescent state of functional hematopoietic stem cells (HSCs) [14,15] . Malignant
brain tumor derived gangliosides inhibited hematopoiesis at different stages of differentiation and resulted
in bone marrow hypoplasia [16,17] . PGE2 regulates hematopoiesis in a dose and time-dependent manner and
modulates hematopoiesis as negative and positive feedback control [18,19] . The immunosuppressive, IL-10 is
found to contribute its inhibitory impact in hematolymphopoiesis during various pathological conditions [20,21] .

Viewing HSCs as the foundation for the immune response we hypothesize that global immune suppression
[22]
during glioma progression might have an important deleterious bearing on synchronized internal signaling
network of hematopoietic machinery that regulates HSCs homeostasis, proliferation, and migration. However,
there is an iota of literature about the status of bone marrow-derived HSCs during glioma condition and/or
immunotherapeutic modulation of HSCs. There has been little success in preventing destructive nature of glioma
either by modulating glioma stem cells or by using genetically engineered stem cells in glioma therapy [23,24] .

HSCs are delineated by their propensity for self-renewal and differentiation into entire committed hematopoietic
lineages. With few exceptions, proper functioning of early hematopoietic stem and progenitor cells are dependent
on c-kit, stem cell antigen-1 (Sca-1) and CD34 mediated signalling system for their self-renewal, proliferation, and
survival [25-27] . On the other hand, Angiopoietin-1 (Ang-1) and tyrosine-protein kinase receptor (Tie-2), the two
important cell surface markers maintain homeostasis of HSCs by regulating molecular crosstalk between HSCs
and bone marrow niche and protect HSCs from pathological conditions [28,29] .

The novel immunomodulatory glycopeptide, T11 target structure/Sheep-Lymphocyte function-associated
antigen-3/CD58 (T11TS/SLFA-3/S-CD58) , has been delineated in our lab for its multipotent anticancer
[30]
activities against N-ethyl-N-nitrosourea (ENU) induced glioma-bearing rat model and also in vitro human
glioma samples . Typically T11TS mediated eradication of glioma is due to the simultaneous rejuvenation
[31]
of peripheral and intracranial immune system which was profoundly suppressed due to gliomagenic
secretion of immunosuppressive cytokines such as IL-10, TGF-β, IL-4, and PGE2, etc. T11TS imparts
immune-potentiation by activating T-lymphocytes , NK cells , macrophage (MФ) , Neutrophils
[30]
[33]
[32]
[34]