Adenosine Blockage in Tumor Microenvironment and Improvement of Cancer Immunotherapy

Immunotherapy has been introduced into cancer treatment methods, but different problems have restricted the efficacy of these protocols in clinical trials such as the presence of various immunomodulatory factors in the tumor microenvironment. Adenosine is an immunosuppressive metabolite produced by the tumor to promote growth, invasion, metastasis, and immune evasion. Many studies about adenosine and its metabolism in cancer have heightened interest in pursuing this treatment approach. It seems that targeting the adenosine pathway in combination with immunotherapy may lead to efficient antitumor response. In this review, we provide information on the roles of both adenosine and CD73 in the immune system and tumor development. We also describe recent studies about combination therapy with both purinergic inhibitors and other immunotherapeutic methods.

Listeria monocytogenes activated dendritic cell based vaccine for prevention of experimental tumor in mice

The use of dendritic cells [DCs] as a cellular adjuvant provides a promising approach in immunotherapy of cancer. It has been demonstrated that Listeria monocytogenes activated DCs pulsed ex vivo with tumor antigens trigger a systemic Th1-biased specific immune response and a single dose of this vaccine will cause a considerable anti tumor immunity. The present study was designed to evaluate the ability of multiple doses of tumor antigen-pulsed DCs, matured in the presence of Listeria monocytogenes components in induction of a potent anti-tumor response and the prevention of tumor formation in an experimental model. Bone-marrow derived DCs [BMDCs] were cultured in the presence of GM-CSF and IL-4. After 5 days, tumor lysates with/without Listeria monocytogenes lysate were added to the culture media for another 2 days. Mice received mature and tumor antigen pulsed dendritic cells subcutaneously in 3 groups. Tumor growth was monitored and two weeks after immunotherapy, cytotoxic activity of CD8+ T cells was evaluated in different groups. According to the findings, repeated doses of vaccine did not lead to a significant increase in the activity of cytotoxic T cells and decreased tumor growth of immunized animals. The current study suggests that increased doses of vaccine do not have sufficient efficiency for prevention of tumor induction. Generation of T regulatory responses upon repeated doses of such vaccines should be considered in future investigations

[Evaluation of different Listeria monocytogenes components on dendritic cells for eliciting TH1 response]

Dendritic cells [DCs] play a critical role in the beginning and in the course of immune responses. By observing. Considering the defect in these cells in patients with tumor malignancy. In recent years there has been considerable interests in correction and use of these cells. In our prvious studies we showed that lysate of Listeria monocytogenese can induce maturation of dendritic cells, and induce TH1 response and increase the survival of tumor in an experimental model. The main objective in the present study is to evaluate the effects of different constituents of Listeria monocytogenes on DCs and their efficiency to induce TH1 response. After preparation of different components of Listeria monocytogenese [lysate of Listeria monocytogenes, protein and nucleic acid components], mouse bone marrow cells were cultured for 5 days in the presence of IL-4 and GM-CSF and treated with different components of Listeria for another 2 days. DCs were evaluated for the expression of Co-stimulatory molecules, MHC Class II molecules and Cytokine secretion. The results showed that, all of the components are able to mature DCs efficiently and induce TH1 response. But dendritic cells matured with protein components shift the response to TH1 more efficiently. Our findings indicated that dendritic cell maturation protein components of Listeria monocytogenese shift the response to TH1 more efficiently and may have beneficial effects in cancer immunotherapy

Dendritic cell maturation with CpG for tumor immunotherapy

Bacterial DNA has immunostimulatory effects on different types of immune cells such as dendritic cells [DCs]. Application of DCs as a cellular adjuvant represents a promising approach in the immunotherapy of infectious disease and cancers. To investigate the effect of tumor antigen pulsed DCs in the presence of CpG-1826 in treatment of a murine model of cancer. WEHI-164 cells [Balb/c derived fibrosarcoma cell line] were injected subcutaneously in the right flank of mice. Bone marrow cells were cultured in the presence of GM-CSF and IL-4. After 5 days, tumor lysate, CpG-1826, and oligodeoxynucleosides, as control, were added to the culture media and incubated for 2 days. Cytokine production in DCs culture media was measured by ELISA. Then DCs were injected subcutaneously around the tumor site in the right flank of mice. Tumor growth rate was monitored in case and control groups. Two weeks after DCs immunotherapy, cytotoxic assay was conducted using various amounts of effector [splenic T cells] and target cells [WEHI-164 or CT26] for 6 h. Immunotherapy with DCs treated with CpG led to a significant increase in the activity of cytotoxic T cells and decreased tumor growth in immunized mice. In the control group which received DCs without CpG treatment, no change in cytotoxic activity and tumor growth rate was detected. The current study suggests that specific anti tumor immune responses can be induced by DCs matured with CpG and proposes CpG usage in DCs targeted clinical strategies