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Combining SiRPα decoy–coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells
Evangelos Stefanidis, … , George Coukos, Melita Irving
Evangelos Stefanidis, … , George Coukos, Melita Irving
Published June 3, 2024
Citation Information: J Clin Invest. 2024;134(11):e161660. https://doi.org/10.1172/JCI161660.
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Research Article Immunology Article has an altmetric score of 72

Combining SiRPα decoy–coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells

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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.

Authors

Evangelos Stefanidis, Aikaterini Semilietof, Julien Pujol, Bili Seijo, Kirsten Scholten, Vincent Zoete, Olivier Michielin, Raphael Sandaltzopoulos, George Coukos, Melita Irving

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Figure 4

CV1-Fc produced by TCR-T cells augments tumor cell phagocytosis by macrophages and increases control of tumor outgrowth.

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CV1-Fc produced by TCR-T cells augments tumor cell phagocytosis by macro...
(A) Schematic of tumor cell phagocytosis by macrophages (human MDMs) in the presence of supernatant from SiRPα-Fc–engineered T cells. (B) Tumor cell phagocytosis by MDMs in the presence of supernatant from SiRPα-Fc–engineered T cells (n ≥3). (C) Schematic of triple coculture of tumor cells, macrophages (MDMs), and engineered T cells. (D) Tumor cell phagocytosis by MDMs in triple cocultures with SiRPα-Fc–secreting T cells (n ≥3). (E) Schematic of the Winn assay. (F) Control of A375 outgrowth (left) and survival (right) in a Winn assay with SiRPα decoy–coengineered A97L–T cells (n = 5; data are representative of 2 independent studies). (G) Control of Me275 outgrowth (left) and survival (right) in a Winn assay with SiRPα decoy–coengineered A97L–T cells (n = 6; data are representative of 2 independent studies). Statistical analysis was done by 1-way ANOVA (B and D), 2-way ANOVA (F, left, and G, left), or Mantel-Cox (F, right, and G, right) with correction for multiple comparisons by post hoc Tukey’s test (B and D; and F and G: CV1-Fc versus TCR + inSiRPα-Fc) or post hoc Šidák’s test (F and G: TCR + inSiRPα-Fc vs. TCR + CV1-SiRPα-Fc). *P < 0.05; **P < 0.01; ***P < 0.001; ****P< 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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