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Gamma delta T cells are activated by polysaccharide K (PSK) and contribute to the anti-tumor effect of PSK.

ABSTRACT: Polysaccharide K (PSK) is a widely used mushroom extract that has shown anti-tumor and immunomodulatory effects in both preclinical and clinical studies. Therefore, it is important to understand the mechanism of actions of PSK. We recently reported that PSK can activate toll-like receptor 2 and enhances the function of NK cells. The current study was undertaken to study the effect of PSK on gamma delta (??) T cells, another important arm of the innate immunity. In vitro experiments using mouse splenocytes showed that ?? T cells produce IFN-? after treatment with PSK and have up-regulated expression of CD25, CD69, and CD107a. To investigate whether the effect of PSK on ?? T cells is direct or indirect, purified ?? T cells were cultured either alone or together with bone marrow-derived DC in a co-culture or trans-well system and then stimulated with PSK. Results showed that direct cell-to-cell contact between ?? T cells and DC is required for optimal activation of ?? T cells. There was also reciprocal activation of DC by PSK-activated ?? T cells, as demonstrated by higher expression of costimulatory molecules and enhanced production of IL-12 by DC in the presence of ?? T cells. PSK can also co-stimulate ?? T cells with anti-TCR and anti-CD3 stimulation, in the absence of DC. Finally, in vivo treatment with PSK activates ?? T cells among the tumor infiltrating lymphocytes, and depleting ?? T cells during PSK treatment attenuated the anti-tumor effect of PSK. All together, these results demonstrated that ?? T cells are activated by PSK and contribute to the anti-tumor effect of PSK.

SUBMITTER: Inatsuka C

PROVIDER: S-EPMC3727629 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Gamma delta T cells are activated by polysaccharide K (PSK) and contribute to the anti-tumor effect of PSK.

Inatsuka Carol C Yang Yi Y Gad Ekram E Rastetter Lauren L Disis Mary L ML Lu Hailing H

Cancer immunology, immunotherapy : CII 20130518 8

Polysaccharide K (PSK) is a widely used mushroom extract that has shown anti-tumor and immunomodulatory effects in both preclinical and clinical studies. Therefore, it is important to understand the mechanism of actions of PSK. We recently reported that PSK can activate toll-like receptor 2 and enhances the function of NK cells. The current study was undertaken to study the effect of PSK on gamma delta (γδ) T cells, another important arm of the innate immunity. In vitro experiments using mouse s ...[more]

PMID: 23685781

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Project description:Interactions between immune and tumor cells in the tumor microenvironment (TME) often impact patient outcome, yet remain poorly understood. In addition, the effects of biophysical features such as hypoxia [low oxygen (O2)] on cells within the TME may lead to tumor evasion. Gamma delta T cells (γδTcs) naturally kill transformed cells and are therefore under development as immunotherapy for various cancers. Clinical trials have proven the safety of γδTc immunotherapy and increased circulating γδTc levels correlate with improved patient outcome. Yet, the function of γδTc tumor infiltrating lymphocytes in human breast cancer remains controversial. Breast tumors can be highly hypoxic, thus therapy must be effective under low O2 conditions. We have found increased infiltration of γδTc in areas of hypoxia in a small cohort of breast tumors; considering their inherent plasticity, it is important to understand how hypoxia influences γδTc function. In vitro, the cell density of expanded primary healthy donor blood-derived human γδTc decreased in response to hypoxia (2% O2) compared to normoxia (20% O2). However, the secretion of macrophage inflammatory protein 1α (MIP1α)/MIP1β, regulated on activation, normal T cell expressed and secreted (RANTES), and CD40L by γδTc were increased after 40 h in hypoxia compared to normoxia concomitant with the stabilization of hypoxia inducible factor 1-alpha protein. Mechanistically, we determined that natural killer group 2, member D (NKG2D) on γδTc and the NKG2D ligand MHC class I polypeptide-related sequence A (MICA)/B on MCF-7 and T47D breast cancer cell lines are important for γδTc cytotoxicity, but that MIP1α, RANTES, and CD40L do not play a direct role in cytotoxicity. Hypoxia appeared to enhance the cytotoxicity of γδTc such that exposure for 48 h increased cytotoxicity of γδTc against breast cancer cells that were maintained in normoxia; conversely, breast cancer lines incubated in hypoxia for 48 h prior to the assay were largely resistant to γδTc cytotoxicity. MICA/B surface expression on both MCF-7 and T47D remained unchanged upon exposure to hypoxia; however, ELISAs revealed increased MICA shedding by MCF-7 under hypoxia, potentially explaining resistance to γδTc cytotoxicity. Despite enhanced γδTc cytotoxicity upon pre-incubation in hypoxia, these cells were unable to overcome hypoxia-induced resistance of MCF-7. Thus, such resistance mechanisms employed by breast cancer targets must be overcome to develop more effective γδTc immunotherapies.

Dataset Information

Gamma delta T cells are activated by polysaccharide K (PSK) and contribute to the anti-tumor effect of PSK.

Publications

Gamma delta T cells are activated by polysaccharide K (PSK) and contribute to the anti-tumor effect of PSK.

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