MODULATING THE MICROENVIRONMENT FOR ACTIVATION OF THE ANTI-TUMOR IMMUNE RESPONSE: RECEPTORS AND MACROPHAGE-TRAINED IMMUNITY

INTRODUCTION AND OBJECTIVES: Immunotherapy is an approach to treating cancer by generating or augmenting the body's immune system to target and eliminate cancer cells. Trained immunity is a newer concept in immunotherapy, particularly interesting for the modulation of the tumor microenvironment, due to its ability to reprogram immune responses. The term infers a "memory" characteristic in innate immunity, an increased response of myeloid cell populations to previous insults. Currently, in most solid tumors, the success of immunotherapy is still limited, due to the dynamic interactions between immune and tumor cells, which make the tumor microenvironment suppressive to the immune response. Improving tumor immunotherapy aims to reduce the huge proportion of unfavorable outcomes associated with this disease. Here, we demonstrate that the administration of trained macrophages is capable of partially reverse the tumor-suppressive microenvironment related to therapeutic failure. MATERIAL AND METHODS: We utilized a melanoma model, based on the subcutaneous injection of B16-OVA cells, that allows analysis of the induction of the adaptive immune responses. 12 C57BL/6 animals were used, mainly with 1 animal per treatment group. We generated trained bone marrow-derived macrophages (BMDMs) in vitro, with administration of soluble pattern recognition receptors (PRRs) ligands, and assessed the training by proinflammatory cytokines (TNF and IL-6) secretion after cell challenge. These trained macrophages were further incubated for 6 hours with Poly I:C (TLR3 agonist) before subcutaneous administration adjacent to the tumors. After 14 days of treatment, the animals were euthanized, their tumors excised and evaluated for the major tumor-infiltrating leukocytes by flow cytometry. RESULTS AND CONCLUSION: By measuring the size of the palpable tumors on the skin of the animals, we observed a tendency (statistically non-significant) towards inhibition of tumor progression in the mice treated with trained BMDMs and challenged with Poly I:C (n=1) or injected with a solution containing the drug Fucoidan (scavenger receptor modulator (n=2)). Moreover, these animals had an increase in the total percentage of tumor-infiltrating lymphocytes, with a higher frequency of proinflammatory cells, such as TCD8+, NKs, macrophages and activated dendritic cells. However, it also presented a higher frequency of cells with suppressive phenotype, i.e. myeloid-derived suppressor cells (MDSCs). In order to improve these results, we reached other approaches to induce trained immunity described in the literature, specifically, the use of particulate ligands, as β-glucan. In this sense, we improved the secretion of proinflammatory cytokines (p < 0,05) by these macrophages during training. Therefore, it’s expected that the state of the tumor microenvironment will be reversed from immunosuppressive to immunostimulatory by administering these “hyper-inflammatory” macrophages.