Combining SiRPα decoy-coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells.
Details
Serval ID
serval:BIB_36EE50DF7CA8
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Combining SiRPα decoy-coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells.
Journal
The Journal of clinical investigation
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Publication state
Published
Issued date
23/04/2024
Peer-reviewed
Oui
Volume
134
Number
11
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Publication Status: epublish
Abstract
The adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells (ACT) targeting the HLA-A2-restricted cancer-testis epitope NY-ESO-1157-165 (A2/NY) has yielded favorable clinical responses against several cancers. Two approaches to improve ACT are TCR affinity optimization and T cell coengineering to express immunomodulatory molecules that can exploit endogenous immunity. By computational design we previously developed a panel of binding-enhanced A2/NY-TCRs including A97L, which augmented the in vitro function of gene-modified T cells as compared with WT. Here, we demonstrated higher persistence and improved tumor control by A97L-T cells. In order to harness macrophages in tumors, we further coengineered A97L-T cells to secrete a high-affinity signal regulatory protein α (SiRPα) decoy (CV1) that blocks CD47. While CV1-Fc-coengineered A97L-T cells mediated significantly better control of tumor outgrowth and survival in Winn assays, in subcutaneous xenograft models the T cells, coated by CV1-Fc, were depleted. Importantly, there was no phagocytosis of CV1 monomer-coengineered T cells by human macrophages. Moreover, avelumab and cetuximab enhanced macrophage-mediated phagocytosis of tumor cells in vitro in the presence of CV1 and improved tumor control upon coadministration with A97L-T cells. Taken together, our study indicates important clinical promise for harnessing macrophages by combining CV1-coengineered TCR-T cells with targeted antibodies to direct phagocytosis against tumor cells.
Keywords
Animals, Humans, Mice, Antigens, Differentiation/immunology, Antigens, Neoplasm/immunology, CD47 Antigen/immunology, Cell Line, Tumor, HLA-A2 Antigen/immunology, HLA-A2 Antigen/genetics, Immunotherapy, Adoptive, Macrophages/immunology, Macrophages/metabolism, Phagocytosis, Receptors, Antigen, T-Cell/immunology, Receptors, Antigen, T-Cell/metabolism, Receptors, Immunologic/immunology, Receptors, Immunologic/metabolism, Receptors, Immunologic/genetics, T-Lymphocytes/immunology, Xenograft Model Antitumor Assays, Male, Female, Cancer immunotherapy, Immunology, Innate immunity, T cells, Therapeutics
Pubmed
Web of science
Open Access
Yes
Create date
13/06/2024 15:04
Last modification date
20/08/2024 6:22