Abstract 1349: Deletion of host-derived GPNMB positively regulates anti-tumor response by reprogramming tumor-associated macrophages.

Abstract Recent work has suggested that poor T cell infiltration and activation in non-responding tumors to immunotherapy is associated with immunosuppressive tumor-associated macrophages (TAMs). GPNMB is a glycosylated type I transmembrane protein found to be upregulated in multiple human cancers, with several cancer mouse models showing that it is expressed in an anti-inflammatory, highly differentiated subtype of TAMs. Analysis of human breast cancer single-cell RNA-seq data showed GPNMB to be upregulated in the myeloid compartment of non-responders to anti-PD1 therapy, suggesting a possible salvage immune suppressive role. Full knockout (KO), Vav1-Cre, and LysM-Cre GPNMB mouse models were generated to study the effect of this gene on tumor progression in the subcutaneous B16.SIY and orthotopic EO771 tumor systems. KO of GPNMB in the host, but not in tumor cells, led to markedly reduced B16.SIY and EO771 tumor growth. Tumors from KO hosts had more CD8+ T cells, MHC-IIhigh CD86+ macrophages, and enhanced CD8+ T cells activation. CD8+ T cell depletion or in vivo IFN-γ blockade eliminated the difference in the pro-inflammatory macrophages, and depletion of all T cells led to complete loss of tumor control. Single-cell RNA-seq revealed no differences at baseline between WT and KO mice in bone marrow, spleen, and lymph nodes, suggesting GPNMB deficiency did not disrupt normal tissue function. However, it showed significant differences in immune cells isolated from tumors. Relative to WT, KO mice had expanded populations of pro-inflammatory macrophages expressing IFN-induced genes, and smaller populations of macrophages expressing either mitochondrial genes involved in oxidative phosphorylation or lipid metabolism genes. The KO also led to significant changes in the transcriptional profiles of two anti-inflammatory subtypes of macrophages, high in Spp1 and C1q expression respectively. IFN-induced, complement, and inflammasome related genes were upregulated in the KO. Macrophages isolated from tumors of KO mice showed decreased suppression of CD8+ T cells in an in vitro co-culture assay. To better understand the role of host versus bone-marrow-derived GPNMB for tumor control, we generated bone-marrow (BM) chimeras where GPNMB was deleted either from the host only or from the BM only. Slower tumor growth was observed when GPNMB was deleted from the host, and faster tumor growth when GPNMB was deleted from the BM. Conditional deletion of GPNMB in hematopoietic cells using Vav1-Cre mice showed no tumor control, while its conditional deletion in myeloid cells using LysM-Cre mice showed significant reduction in tumor growth. Taken together with previous data showing that the LysM-Cre targets populations of tissue-resident macrophages that the Vav1-Cre does not, those results suggest a potential role of GPNMB-expressing tissue resident-macrophages in shaping anti-tumor immunity. Citation Format: Ruxandra Tonea, Samantha J. Riesenfeld, Thomas Frank Gajewski, . Deletion of host-derived GPNMB positively regulates anti-tumor response by reprogramming tumor-associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1349.