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Supplementary Figure 6 from PSGL-1 Blockade Induces Classical Activation of Human Tumor-associated Macrophages

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posted on 2023-10-26, 14:20 authored by Kevin Kauffman, Denise Manfra, Dominika Nowakowska, Mohammad Zafari, Phuong A. Nguyen, Ryan Phennicie, Elisabeth H. Vollmann, Brian O'Nuallain, Sara Basinski, Veronica Komoroski, Kate Rooney, Elizabeth K. Culyba, Joseph Wahle, Carola Ries, Michael Brehm, Steve Sazinsky, Igor Feldman, Tatiana I. Novobrantseva

Evaluation of activation conditions on multiple primary cells and cell lines.

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Verseau Therapeutics

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ARTICLE ABSTRACT

The immune suppressive microenvironment is a major culprit for difficult-to-treat solid cancers. Particularly, inhibitory tumor-associated macrophages (TAM) define the resistant nature of the tumor milieu. To define tumor-enabling mechanisms of TAMs, we analyzed molecular clinical datasets correlating cell surface receptors with the TAM infiltrate. Though P-selectin glycoprotein ligand-1 (PSGL-1) is found on other immune cells and functions as an adhesion molecule, PSGL-1 is highly expressed on TAMs across multiple tumor types. siRNA-mediated knockdown and antibody-mediated inhibition revealed a role for PSGL-1 in maintaining an immune suppressed macrophage state. PSGL-1 knockdown or inhibition enhanced proinflammatory mediator release across assays and donors in vitro. In several syngeneic mouse models, PSGL-1 blockade alone and in combination with PD-1 blockade reduced tumor growth. Using a humanized tumor model, we observed the proinflammatory TAM switch following treatment with an anti-PSGL-1 antibody. In ex vivo patient-derived tumor cultures, a PSGL-1 blocking antibody increased expression of macrophage-derived proinflammatory cytokines, as well as IFNγ, indicative of T-cell activation. Our data demonstrate that PSGL-1 blockade reprograms TAMs, offering a new therapeutic avenue to patients not responding to T-cell immunotherapies, as well as patients with tumors devoid of T cells. This work is a significant and actionable advance, as it offers a novel approach to treating patients with cancer who do not respond to T-cell checkpoint inhibitors, as well as to patients with tumors lacking T-cell infiltration. We expect that this mechanism will be applicable in multiple indications characterized by infiltration of TAMs.