The tumor microenvironment contains innate immune cells displaying pro-tumor functions such as tumor-associated macrophages (TAMs). TAMs have been shown to be a limiting factor for anticancer therapies inducing resistance to chemo- and immuno-therapies. These TAMs preferentially exhibiting an M2-like phenotype, can also promote cancer cell survival and proliferation, and protect them against immune attacks. It has been shown that the elimination of pro-tumoral TAMs in the tumor, can activate immunity in tumors and overcome resistance to anticancer therapies. However, current strategies aimed at depleting TAMs in the tumor are not specific enough to eliminate only pro-tumor TAMs and thus may lead to severe adverse effects.
We have produced and patented a monoclonal antibody, called 6-25, which specifically recognises pro-tumor TAMs of chronic lymphocytic leukemia (CLL), called nurse-like cells (NLC), and TAMs in tumors of other types of cancer (lung, breast, melanoma…). We have shown that the 6-25 mAb is not directly toxic for TAMs but is internalized in these cells, allowing us to consider associated toxic tools to kill TAMs in tumors.

We have therefore developed two tools to eliminate TAMs in tumors: an antibody drug conjugate, 6-25-PBD (pyrrolobenzodiazepin) and magnetic nanoparticles associated with the 6-25 mAb, 6-25-MNP. For both projects, in vitro 2D and 3D co-cultures (cancer cells+macrophages) and in vivo tumor mouse models are being developed in the team in order to demonstrate proof of concept for targeting and eliminating pro-tumor TAMs in tumors particularly in lung cancer models. The prospect is to combine our tools with current treatments, in order to improve responses to classic treatments and avoid relapses.

Moreover, since the target of the 6-25 mAb is only expressed by pro-tumor TAMs including NLC (correlation of NLC target expression with CLL aggressiveness), studying the biology of this target could lead to fundamental discoveries on the pro-tumor functions of TAMs in cancer in general. Thanks to multi-omics characterization and the in vitro model mimicking the microenvironment of lymph nodes in CLL, we can also study the physical cell interactions between TAMs and cancer cells and model them mathematically, in collaboration with people of the subgroups of Vera Pancaldi and Malvina Marku.

1- Spheroid of A549 cell line in green (lung cancer) and macrophages (red: CMTMR; blue: CD206; white: Folr2) 2- Trogocytosis between Nurse like cell and CLL cell in 2D co-culture (red: PKH26 for NLC; blue: cell tracer vio for CLL cell; green: folate-FITC).

Selected Papers and patents in the field:

Patent Inserm WO2018/020000.

M Poupot, M Tosolini, L Ysebaert, JJ Fournié, P Rochaix, P Brousset. 2018. “Antibodies targeting tumor associated macrophages and uses thereof”

• Verstraete, N., Marku, M., Domagala, M., Arduin, H., Bordenave, J., Fournié, J.-J., Ysebaert, L., Poupot, M., & Pancaldi, V. 2023. An Agent-Based Model of Monocyte Differentiation into Tumour-Associated Macrophages in Chronic Lymphocytic Leukemia. iScience May 19;26(6). https://doi.org/10.1016/j.isci.2023.106897
• Domagala M, Ysebaert L, Ligat L, Lopez F, Fournié JJ, Laurent C, Poupot M. 2021. IL-10 Rescues CLL Survival through Repolarization of Inflammatory Nurse-like Cells. Cancers. Dec 21;14(1):16. https://doi:10.3390/cancers14010016.
  Domagala M, Laplagne C, Leveque E, Laurent C, Fournié JJ, Espinosa E, Poupot M. 2021. Cancer Cells Resistance Shaping by Tumor Infiltrating Myeloid Cells. Cancers. Jan 13(2): 165-195. https://doi.org/10.3390/cancers13020165.
• Marku M, Verstraete N, Raynal F, Madrid-Mencia M, Domagala M, Fournié JJ, Ysebaert L, Poupot M, Pancaldi V. 2020. Insights on TAM Formation from a Boolean Model of Macrophage Polarization Based on In Vitro Studies. Cancers. Dec 12(12): 3664-3687. https://doi.org/10.3390/cancers12123664.
• Laplagne C, Domagala M, Le Naour A, Quemerais C, Hamel D, Fournié JJ, Couderc B, Bousquet C, Ferrand A, Poupot M. 2019. Latest Advances in Targeting the Tumor Microenvironment for Tumor Suppression. Int. J. Mol. Sci. Sep 23;20(19).
• Boissard F, Tosolini M, Ligat L, Quillet-Mary A, Lopez F, Fournié JJ, Ysebaert L, Poupot M. 2017. Nurse-like cells promote CLL survival through LFA-3/CD2 interactions. Oncotarget. 8(32):52225-36.
• Boissard F, Laurent C, Ramsay AG, Quillet-Mary A, Fournié JJ, Poupot M*, Ysebaert L*. 2016. Nurse-like cells impact on disease progression in chronic lymphocytic leukemia. Blood Cancer J. Jan 15;6:e381. https://doi:10.1038/bcj.2015.108.
• Boissard F, Fournié JJ, Quillet-Mary A, Ysebaert L, Poupot M. 2015. Nurse-like cells mediate ibrutinib resistance in chronic lymphocytic leukemia patients. Blood Cancer J. Oct 2;5:e355. https://doi:10.1038/bcj.2015.74
• Boissard F, Fournié JJ, Ysebaert L, Poupot M. 2015. Nurse Like Cells: Chronic Lymphocytic Leukemia Associated Macrophages. Leuk. Lymph. Feb; 11:1-3.