T11TS immunotherapy repairs PI3K‐AKT signaling in T‐cells: Clues toward enhanced T‐cell survival in rat glioma model

Abstract

Malignant glioma is the most fatal of astrocytic lineage tumors despite therapeutic advances. Onset and progression of gliomas is accompanied by severe debilitation of T-cell defense and T-cell survival. One of the chief contributors to T-cell survival downstream of activation is the PI3K-AKT pathway. Our prior studies showed that the novel immunotherapeutic molecule T11-target structure (T11TS) blocks T-cell apoptosis in glioma. We also showed activation of immunological synapse components and calcineurin-NFAT pathway following T11TS immunotherapy of glioma-bearing rats. This lead to investigations whether such T-cell activation upon T11TS therapy translates into activation of downstream PI3K/AKT signals which may be related to observed blockade of T-cell apoptosis. For the purpose, we assessed by flowcytometry and immunoblotting, expressions of PI3K, PDK1, AKT, p-AKT, and PTEN in splenic T-cells of normal, experimentally-induced glioma-bearing rats and glioma-bearing rats receiving first, second and third doses of T11TS. We also determined comparative nuclear translocation of NF-κB across groups. We found significant increases in T-cell expressions of PDK1, PI3K, and p-AKT in T11TS-treated animal groups compared to sharp downregulations in glioma. AKT levels remained unchanged across groups. PTEN levels declined sharply after T11TS immunotherapy. T11TS also caused enhanced NF-κB translocation to the T-cell nucleus compared to glioma group. Results showed heightened activation of the PI3K-AKT pathway in glioma-bearing rats following T11TS immunotherapy. These results illustrate the novel role of T11TS immunotherapy in ameliorating the PI3K pathway in T-cells in glioma-bearing animals to enhance T-cell survival, according greater defense against glioma. The study thus has far-reaching clinical outcomes.

T11TS immunotherapy augments microglial and lymphocyte protective immune responses against Cryptococcus neoformans in the brain

“…The glycopeptides T11TS was isolated from sheep erythrocyte (SRBC) membranes by ion exchange chromatography on a DEAE‐cellulose column and eluted with a five‐gradient system . The third elute fraction (EF‐III) containing T11TS was selected for administration.…”

“…10 000 events were acquired and analysed for each sample. Values indicated in “Results” are the mean of six individual studies with SD calculated on each mean value …”

“…Previous publications with T11TS have proposed that in glioma‐bearing rats, T11TS promotes proliferation of the T cells and also favours the T cell survival by inhibition of apoptosis through both the extrinsic and intrinsic apoptotic pathways . Further studies have also highlighted that immunotherapy with T11TS caused activation of T cell CD2‐mediated calcineurin‐NFAT pathway and also modulates PI3K‐AKT survival pathway favouring T cell survival and proliferation by immunotherapy with T11TS in T cells . T11TS not only stimulates the peripheral immune system but also rejuvenates the haematopoietic stem cells, the mother of all immune cells .…”

“…17 Further studies have also highlighted that immunotherapy with T11TS caused activation of T cell CD2-mediated calcineurin-NFAT pathway 10 and also modulates PI3K-AKT survival pathway favouring T cell survival and proliferation by immunotherapy with T11TS in T cells. 18 T11TS not only stimulates the peripheral immune system but also rejuvenates the haematopoietic stem cells, the mother of all immune cells. 19 Previous studies with T11TS in different models like generalized demodicosis in dogs 20 and canine pyoderma 21 have showed that potent immune suppression was reversed to total immune restoration and potentiation.…”

“…The previous manoeuvres have been documented mainly in glioma model 9,10,[13][14][15][16][17][18]22,23 and also in infected canine pyoderma 20 and demodicosis. 21 Noting that this profound immune potentiating molecule not only acts in glioma but also in infected models, we tried immunotherapy with T11TS in the Cryptococcal model, which have not been attempted before.…”