ABSTRACT
Occupying more than half of the tumor volume in a variety of solid tumors, tumor-associated macrophages (TAMs) are an important part of the tumor microenvironment (TME) with high plasticity and heterogeneity. In the early stages of tumor development, TAMs mediate antitumor effect through phagocytosis and their antioxidant functions. However, in order to meet the needs of self-renewal and proliferation, malignant tumor cells continuously adjust their metabolic patterns, leading to the accumulation of metabolites such as lactate, reactive oxygen species, nitric oxide, arachidonic acid and prostaglandin in the TME, which results in the changes in its inflammatory profiles, thereby altering the metabolism and function of TAMs and ultimately promoting the tumor development. Therefore, further understanding of the metabolism and immune responses of TAMs in the TME during tumor progression is warranted and the investigation may lead to identification of novel potential targets for cancer immunotherapy. This review aims to clarify the close relationship between TAMs metabolism and TME immune response, to reveal the mechanism of tumor immunosuppression produced by TAMs metabolism, and to provide new treatment ideas and approaches for tumor immunotherapy.
ABSTRACT
BACKGROUND: As an attempt to develop a strategy to improve the protective immune response to GM-CSF-secreting CT26 (GM-CSF/CT26) tumor vaccine, we have investigated whether the apoptogenic treatment of GM-CSF/CT26 prior to vaccination enhances the induction of anti-tumor immune response in mouse model. METHODS: A carcinogen- induced mouse colorectal tumor, CT26 was transfected with GM-CSF gene using a retroviral vector to generate GM-CSF-secreting CT26 (CT26/GM-CSF). The CT26/GM-CSF was treated with gamma-irradiation or mitomycin C to induce apoptosis and vaccinated into BALB/c mice. After 7 days, the mice were injected with a lethal dose of challenge live CT26 cells to examine the protective effect of tumor vaccination in vivo. RESULTS: Although both apoptotic and necrotic CT26/GM-CSF vaccines were able to enhance anti-tumor immune response, apoptotic CT26/GM-CSF induced by pretreatment with gamma-irradiation (50,000 rads) was the most potent in generating the anti-tumor immunity, and thus 100% of mice vaccinated with the apoptotic cells remained tumor free for more than 60 days after tumor challenge. CONCLUSION: Apoptogenic pretreatment of GM-CSF-secreting CT26 tumor vaccine by gamma-irradiation (50,000 rads) resulted in a significant enhancement in inducing the protective anti-tumor immunity. A rapid induction of apoptosis of CT26/GM-CSF tumor vaccine at the vaccine site might be critical for the enhancement in anti-tumor immune response to tumor vaccine.