PSGL-1 Blockade Induces Classical Activation of Human Tumor-associated Macrophages.

Autor:	Kauffman K; Verseau Therapeutics, Auburndale, Massachusetts., Manfra D; Verseau Therapeutics, Auburndale, Massachusetts., Nowakowska D; Verseau Therapeutics, Auburndale, Massachusetts., Zafari M; Verseau Therapeutics, Auburndale, Massachusetts., Nguyen PA; Verseau Therapeutics, Auburndale, Massachusetts., Phennicie R; Verseau Therapeutics, Auburndale, Massachusetts., Vollmann EH; Verseau Therapeutics, Auburndale, Massachusetts., O'Nuallain B; Verseau Therapeutics, Auburndale, Massachusetts., Basinski S; Verseau Therapeutics, Auburndale, Massachusetts., Komoroski V; Verseau Therapeutics, Auburndale, Massachusetts., Rooney K; Verseau Therapeutics, Auburndale, Massachusetts., Culyba EK; Verseau Therapeutics, Auburndale, Massachusetts., Wahle J; Verseau Therapeutics, Auburndale, Massachusetts., Ries C; Dr. Carola Ries Consulting, Penzberg, Germany., Brehm M; University of Massachusetts Medical School, Worcester, Massachusetts., Sazinsky S; Verseau Therapeutics, Auburndale, Massachusetts., Feldman I; Verseau Therapeutics, Auburndale, Massachusetts.; Currently employed by Moderna Therapeutics, Cambridge, Massachusetts., Novobrantseva TI; Verseau Therapeutics, Auburndale, Massachusetts.; Currently employed by Moderna Therapeutics, Cambridge, Massachusetts.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2023 Oct 26; Vol. 3 (10), pp. 2182-2194.
DOI:	10.1158/2767-9764.CRC-22-0513
Abstrakt:	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. Significance: 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. (© 2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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