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JHU083-induced glutamine antagonism causes extensive reprogramming of TILs. A, UMAP plot showing lymphocytic cell subsets identified from scRNA-seq analysis of CD45+ cells isolated from B6CaP tumors (JHU083-treated vs. control). B, UMAP density plots showing all NK and T cells. C, Dot plots of normalized expression of selected marker genes in T and NK cell subsets identified in A. D, Changes in proportions of NK cell subsets, stem cell–like CD8+ T cells, and CD4− Tregs from scRNA-seq (n = 3/group). E, Surface and intracellular expression of stem-like CD8+ T cells and Foxp3+ percentage population in B6CaP and MB49 tumors (n = 7/8 per group). F, Schematic workflow of T cell coculture with DON-pretreated human primary macrophages. G, CD8+ T cell proliferation measurement using autologous CD8+ T cells isolated from human PBMCs and cocultured with monocyte-derived macrophages pretreated with DON either during differentiation (days 0–9) or during polarization (days 5–9) phase. H, gMFI of TNF and IFNγ in cocultured autologous CD8+ T cells with DON pretreated monocyte-derived macrophages, and (I) Tumor volume measurement of MB49 and B6CaP tumors during the therapeutic window. Briefly, following the development of palpable tumors, tumor-bearing C57BL/6J mice were injected every third day with anti-PD1 alone or in combination with daily oral gavage of JHU083. The data are presented as mean values ± SEM. Statistical analyses were performed using either t test or a two-way ANOVA using Bonferroni’s multiple comparisons (*, P P P P
Praharaj et al. (Tue,) studied this question.