Background: Glycoprotein non-metastatic B (GPNMB) is expressed by tumor cells and myeloid populations, but its macrophage-specific functions in solid tumors remain unclear. Methods: Using the E0771 breast cancer model, we compared tumor growth and immunity in Gpnmb+/- and Gpnmb-/- mice. We combined flow cytometry, immunofluorescence imaging, and single-cell RNA-seq to profile myeloid and lymphoid compartments. We tested CD8 dependence by antibody-mediated depletion, assessed macrophage–T-cell crosstalk in co-culture with bone marrow-derived macrophages (BMDMs), and evaluated macrophage depletion by anti-CSF1R. Results: Loss of host Gpnmb remodeled the tumor microenvironment toward a T cell– inflamed state with increased ratio of effector CD8⁺ T cells and an expansion of CXCL9⁺/MHC-II⁺ macrophages. CD8 depletion abrogated tumor control, establishing CD8 dependence. Spatial analysis revealed that in Gpnmb-/- hosts macrophages and T cells cluster at the tumor margin with a fraction of T cells penetrating the parenchyma, consistent with productive macrophage – T cell organization. In vitro, BMDM – T cell co-cultures did not reproduce GPNMB-dependent defects, suggesting a requirement for in vivo niche cues (e.g., debris efferocytosis/hypoxia/ECM). Across tested cancer models, rejection occurred selectively (e.g., E0771, B16), whereas non-rejecting lines lacked GPNMB⁺ TAMs in our datasets, making them GPNMB-independent. Broad macrophage depletion accelerated tumor growth in both genotypes, consistent with TAM heterogeneity and compensatory myelopoiesis. Conclusions: Host-derived GPNMB organizes an immunosuppressive niche that limits effective CD8⁺ responses. These data favor subset-targeted TAM reprogramming over global depletion and motivate lineage-specific Gpnmb genetics and epistasis tests (e.g., Gpnmb–Trem2) to define mechanism. Therapeutically, GPNMB-targeted approaches, combined with blockade of compensatory myeloid recruitment, should be investigated.
Kateryna Stepaniuk (Thu,) studied this question.