Abstract
Previous studies have demonstrated the beneficial effect of graft-versus-tumor (GVT) following hematopoietic stem cell transplantation (HSCT) on the incidence of leukemia relapse and the overall survival rate of patients with leukemia; however, detailed mechanisms underlying the effects GVT exhibits on solid tumors following allogeneic HSCT are yet to be elucidated. The aim of the present study was to investigate the immune mechanism underlying the effect of interferon (IFN)-γ on GVT following allogeneic HSCT in breast cancer therapy. An in situ breast cancer mouse model was established by injecting 5×104 4T1 cells into the mammary fat pads of BALB/c mice. The 4T1 cells were transfected with the firefly luciferase reporter gene in order to monitor the tumor progression in real time. An allogeneic HSCT model was then established by transplanting bone marrow mononuclear cells from C57BL/6 mice to the BALB/c mice. To investigate the influence of T lymphocyte proliferation following allogeneic bone marrow transplantation, the levels of CD3+CD8+ cytotoxic T lymphocytes (CTLs) and CD4+CD25+ regulatory T cells were determined. In addition, IFN-γ and granzyme B expression levels in splenic lymphocytes were analyzed using flow cytometry. Allogeneic HSCT was found to significantly promote the proliferation and cytotoxicity of CTLs and suppress the growth of breast cancer. Furthermore, the secretory levels of IFN-γ and granzyme B by T cells were elevated following allogeneic HSCT. These results indicated that alloreactive T cells increased the secretion of IFN-γ, which promoted the alloresponse of donor CTLs. In addition, the CTLs produced granzyme B, which exerted a tumor suppressive effect.
Highlights
Graft‐versus‐host disease (GVHD), known as graft‐versus‐tumor (GVT) effects, has been demonstrated to enhance the therapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) in the treatment of leukemia [1]
For HSCT, the BALB/c mice were injected with 0.2 ml phosphate‐buffered saline containing 2.0x105 bone marrow mononuclear cells from female red fluorescent protein (RFP) transgenic C57BL/6‐RFP (H‐2b), C57BL/6 or BALB/c mice via a tail vein injection within 2 h after irradiation
The results revealed that GVT effects are dependent on the IFN‐γ and granzyme B signaling pathways
Summary
Graft‐versus‐host disease (GVHD), known as graft‐versus‐tumor (GVT) effects, has been demonstrated to enhance the therapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) in the treatment of leukemia [1]. The major GVT effectors are cytotoxic T lymphocytes (CTLs), which recognize allogeneic histocompatibility antigens and unique tumor antigens [1]. It is hypothesized that donor CTLs exhibit a cytotoxic effect against minor histocompatibility antigens or tumor‐associated antigens. Regulatory T cells (Tregs) have been demonstrated to protect the host from GVHD by suppressing donor immune cells, and may block antitumor immune responses [5]. IFN‐γ has been found to sensitize tumor cells to CTLs, inhibiting the expansion of tumor cells and upregulating the expression of Fas and major histocompatibility complex (MHC) molecules [6]. IFN‐γ has been hypothesized to function directly on CD8+ T cells to stimulate the development of the CTL response [7,8]. The role of IFN‐γ in graft‐versus‐solid tumor effects remains unclear
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