- Published Abstract Number: 4133
- Autors :
Caroline Mignard, Damien France, Francis Bichat, Nicolas Legrand, Olivier Duchamp (Oncodesign Services, 21000 Dijon – France)
- Abstact :
Tumor-Associated Macrophages (TAMs) play an important role in the development of tumors, modulation of neoangiogenesis, immune suppression, and metastasis. A high infiltration of macrophages in the tumor is also correlated with a poor prognosis in several cancer types. Therefore, they became an attractive target for cancer immunotherapies. Several macrophage-targeting approaches in anticancer therapy are under development, including TAM depletion, inhibition of new TAM differentiation, or re-education of TAM activation for cancer cell phagocytosis. In this presentation, we will share different examples of in vitro assays and in vivo models we are implementing to support preclinical development of novel TAM-targeting strategies. Antibody-dependent cellular phagocytosis (ADCP) has been used to demonstrate one crucial mechanism of action of different antibody (Ab) therapies targeting macrophages. Some of these Ab (including anti-CSF1) have then been tested in syngeneic in vivo tumor models. To reach this goal, we demonstrated that the tumor implantation site in mice (subcutaneous vs orthotopic) could impact the polarization of macrophages (M1 vs M2). Differences in the ratio of M1 and M2 subtypes infiltrating the PAN-02 pancreatic murine tumors were observed, and anti-CSF1 antibodies increased the survival of mice bearing orthotopic Renca murine kidney tumor by eliminating TAMs. Additionally, in xenograft models of human breast tumors in NOD-SCID mice, the eradication of TAMs by anti-CSF1R clearly demonstrated the importance of macrophages in the tumor progression and in the anti-tumor efficacy of Abs mediated by macrophages. By using an orthotopic Hepa1-6 murine liver cancer model, we showed high antitumor efficacy of compounds targeting the STAT6 pathway by reprogramming immunosuppressive TAMs into an M1 phenotype that promotes the induction of a cytotoxic immune response. For compounds displaying no cross-reactivity with murine target, we developed models and characterized the TAMs in breast, colon, melanoma and head & neck PDX and CDX tumors in different huCD34-engrafted mouse models. Altogether, the panel of in vitro assays and in vivo tumor models in OncoTAM should be useful to provide insights on the mechanism of action and antitumor efficacy of novel immune-oncology strategies targeting macrophages.