Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model

Abstract

Lymphoma cells mobilize many mechanisms to evade the immune system. There is substantial evidence that CD4 1 CD25 1 regulatory T cells (Tregs) play a key role in the control of immune evasion. Tregs can transfer cyclic adenosine monophosphate (cAMP) to effector T cells, suggesting an association between Tregs' immune-evasion role and the intracellular cAMP pathway. In this study, we used A20 B-cell lymphoma mice as aggressive tumor models to investigate the mechanism of the depletion of Tregs by low-dose cyclophosphamide (CY, 20 mg/kg). The tumor-bearing mice had longer survival times and slower tumor growth rates following treatment with CY, but its effects were temporary. Along with the depletion of Tregs by low-dose CY treatment, the expression of interleukin-2 (IL-2) in T effector cells increased, and intracellular cAMP concentrations in immune cells decreased. Our study demonstrates the ability of low-dose CY to reverse Tregs-mediated immune evasion in a mouse model. The changes in intracellular cAMP concentrations correlated with the upregulation of effector T cells and the downregulation of Tregs, indicating the close association of cAMP analogs and low-dose CY in the immune therapy of B-cell lymphoma.

Combining low-dose or metronomic chemotherapy with anticancer vaccines

“…Mice bearing A20 lymphomas exhibted a prolonged survival and reduced rates of tumor growth upon treatment with low-dose cyclophosphamide (20 mg/kg) 43 . Bertolini et al 65 also observed a significant inhibition of tumor growth in mice bearing human mantle lymphomas upon the administration of cyclophosphamide in drinking water as a continuous low-dose of 20 mg/kg/day.…”

“…Interventions aimed at enhancing antitumor immune responses based on the depletion or neutralization of Tregs by chemotherapy have been intensively studied. Thus, low-dose cyclophosphamide was found to selectively kill Tregs in vivo, in a murine model of lymphoma 43 . In this setting, effector T cells were activated along with Treg depletion and increased expression of IL-2 43 .…”

“…Thus, low-dose cyclophosphamide was found to selectively kill Tregs in vivo, in a murine model of lymphoma 43 . In this setting, effector T cells were activated along with Treg depletion and increased expression of IL-2 43 . When mice with colon cancer were treated with low-dose cyclophosphamide plus doxorubicin, a significant suppression of tumor growth was associated with Tregs depletion and decreased secretion of TGFβ1 within the tumor microenvironment 44 .…”

Follicular B Lymphomas Generate Regulatory T Cells via the ICOS/ICOSL Pathway and Are Susceptible to Treatment by Anti-ICOS/ICOSL Therapy

“…In mouse models, depletion of Tregs induced decreased lymphoma burden (48). Unfavorable outcome was reported for FL patients with high levels of peripheral blood Tregs (49).…”

A bystander cell-based GM-CSF secreting vaccine synergized with a low dose of cyclophosphamide presents therapeutic immune responses against murine hepatocellular carcinoma

“…It has been demonstrated that chemotherapeutic agents, such as CY, can ameliorate the antitumor effect of tumor vaccines due to immune tolerance. 34 Additionally, the dose range and administration schedule of chemotherapy directly affects the combined therapeutic effect. 22 There is little doubt that a high dose of chemotherapy can also depress the immune system, resulting is a weakened tumor-specific T-cell response.…”