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Enhancing CAR T-cell efficacy against neuroblastoma through MIF inhibition

ABSTRACT: Neuroblastoma is a common pediatric extracranial solid tumor, that arises in the developing sympathetic nervous system. Chimeric antigen receptor (CAR) T-cell therapy has demonstrated promising clinical responses, yet its effectiveness in neuroblastoma benefits only a subset of patients. We evaluated the immunosuppressive secretome of neuroblastoma tumoroids that attenuate CAR T-cells function and efficacy. Secreted proteins were collected from tumoroids and identified by shotgun MS.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Neuroblastoma Cell

DISEASE(S): Neuroblastoma

SUBMITTER: Elisavet Kalaitsidou

LAB HEAD: wei wu

PROVIDER: PXD051044 | Pride | 2025-04-02

REPOSITORIES: Pride

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			Action	DRS
	20210703_EX1_UM8_Sanch035_SA_EXT02_Josephine_039_1.raw	Raw
	20210703_EX1_UM8_Sanch035_SA_EXT02_Josephine_039_2.raw	Raw
	20210703_EX1_UM8_Sanch035_SA_EXT02_Josephine_039_3.raw	Raw
	20210703_EX1_UM8_Sanch035_SA_EXT02_Josephine_691B_1.raw	Raw
	20210703_EX1_UM8_Sanch035_SA_EXT02_Josephine_691B_2.raw	Raw

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Project description:Anti-cancer immunotherapy approaches are increasingly coveted. Chimeric antigen receptor (CAR)-T cell therapy has been shown to be an effective treatment for hematological tumors, but the treatment of solid tumors still lacks effectiveness, due to lower intra-tumor infiltration of CAR-T cells and tumor-induced immunosuppression. Macrophages represent a very large proportion of the tumor environment, participate in many aspects to tumor development and therefore represent interesting therapeutic targets. Macrophages can infiltrate solid tumor tissue and interact with almost all cellular components in the tumor microenvironment. In addition, macrophages can also promote a direct anti-tumor response by phagocyting tumor cells. We have developed macrophages expressing a CAR receptor against the HER2 antigen. The CAR receptor possesses an intracellular domain CD3ζ having homology with the protein FcεRI-γ, which once activated by the recognition antibody-antigen, induces the phagocytic activity of macrophages. 72% of macrophages express the CAR after transduction. CAR-M can specifically phagocyte HER2 coated-beads in a much more effective way than WT macrophages. We have then confirmed the capacity of CAR-M to phagocyte HER2+ cancer cell lines. Co-culture of CAR-M with breast cancer tumoroids (HER2+ or HER2-) has also been performed demonstrating their efficacy in a more complex environment. However, in the tumor microenvironment, due to their plasticity, macrophages tend to adopt an anti-inflammatory phenotype losing their anti-tumor activities. We have therefore developed a combined strategy by inhibiting two proprotein convertases, Furin and PC1/3 in CAR-M. The inhibition of furin or PC1/3 induces an increase in pro-inflammatory markers and maintains macrophage activation in the presence of cancer cells. In addition, HER2+ CAR-M with shFurin or shPC1/3 greatly increases the phagocytic activity on Her2+ beads or Her2+ tumors. These enzymes are therefore phenotypic regulators of macrophages. Our strategy is therefore based on a double activation of tumor-infiltrating macrophages. The first one consists in boosting the phagocytic activity of macrophages by having them express a CAR receptor targeting a tumor antigen. The second allows their reprogramming towards a pro- inflammatory phenotype by the inhibition of Furin and/or PC1/3 proprotein convertases

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Enhancing CAR T-cell efficacy against neuroblastoma through MIF inhibition

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