Fig. 7: Acute Met supplementation promotes CD8+ T cell-mediated tumor control and enhances ICB.
From: Early methionine availability attenuates T cell exhaustion
a, Nuclear NFAT1 quantification in CD44+CD8+ T cells isolated from B16 tumors and respective dLNs at D9 postimplantation (each circle represents one cell, n = 40 cells, n = 5 (Mouse (M)1–M5)). b, Quantification of nuclear NFAT1 in CD44+ CD8+ T cells isolated from B16 tumors after 5 days of peritumoral supplementation of 50 μl HBSS or 61 μM Met per day (each circle represents one cell; n = 40 cells, n = 4 (M1–M4)). c–e, Tumor growth (c) and survival (d) of B16 or MC38 (e) tumor-bearing WT mice, supplemented either with HBSS or 61 μM Met peritumorally for 5 days as in b (n = 10 mice per group). f, B16 tumor growth (left) and survival (right) of WT mice, treated intraperitoneally with IgG isotype or anti-CD8 antibody at D1 and D3 and treated peritumorally with HBSS or Met from D7 to D12 as in b (n = 5 mice per group, representative of two experiments). g, Tumor growth (left) and survival (right) of F420 tumor-bearing Rag1−/− mice injected with B7-H3 CAR-T cells at D0 and peritumorally treated with HBSS or Met from D1 to D6 as in b (n = 5 mice per group). h–j, Tumor growth (h,i) and survival (j) of MC38 tumor-bearing WT mice, treated either with anti-PD-1 or IgG isotype (arrows in i) and fed with either a control (1% Met) or Met-rich (1.5% Met) diet as shown in Extended Data Fig. 10h (n = 10 mice per group). k, Diagram illustrating the impact of Met metabolism on TCR-dependent methylation of KCa3.1, leading to regulation of Ca2+ flux and subsequent activation of NFAT1. Low extracellular Met levels lead to decreased methylation potential, reducing KCa3.1 R350 methylation. This results in increased Ca2+ flux and downstream NFAT1 activation and consequent T cell hyperactivation and exhaustion. Data are mean ± s.d. Unpaired two-tailed Student’s t-test (a), two-way ANOVA (c, e–g, i), and Mantel–Cox log rank test (d–g, j). Statistical analysis of b is described in Methods. Illustrations in k created with BioRender.com.
