Extended Data Fig. 10: NRF2 pathway activation in TME myeloid cells is associated with immunotherapy resistance.
From: Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumours
a, ChIP-X Enrichment Analysis (ChEA) calculated TF regulators for differentially expressed genes in tumoral mo-macs enriched in non-responders (NR cohort) to neoadjuvant immunotherapy (NAIT) for lung cancer (NSCLC, Hu et al., n = 12 patients), compared to responders (R cohort). arranged by adjusted p-value (log q-value). b, ChEA calculated TF regulators for differentially expressed genes in tumoral mo-macs from patients with no clonal T cell expansion (NE cohort) after immune checkpoint blockade (ICB) in breast cancer (BC, Bassez et al., n = 29 patients) compared to macs from patients with clonal expansion (E cohort). c–d, ChEA calculated TF regulators for differentially expressed genes in tumoral mo-macs (c) and peripheral blood CD14+ monocytes (d) enriched in non-responders exhibiting stable disease (SD) to immune checkpoint blockade (ICB) for colorectal cancer (CRC, Chen et al., n = 22 patients) compared to complete response (CR). e, Kaplan-Meier plot depicting overall survival of KP tumor-bearing mice treated with Brusatol in conjunction with anti-PD-1 immunotherapy (n = 8), Brusatol alone (n = 6), anti-PD-1 alone (n = 7), or vehicle (n = 6). f, Kaplan-Meier plot depicting overall survival of KP tumor-bearing mice treated with ML385 in conjunction with anti-PD-1 immunotherapy (n = 6), ML385 alone (n = 5), or vehicle (n = 5). g, Representative histology and tumor burden for KP tumor-bearing Nfe2l2ΔMs4a3 and Nfe2l2fl/fl mice that received Brusatol in conjunction with anti-PD1 (left to right, n = 6,4,5,4,5,5) h, Frequency of NK cells within CD45+ cells (left), and percentage of NK cells expressing CD69 and producing IFNγ (right) in tumor-bearing WT mice treated as indicated. n = 5 mice per group. i, Frequency of CD8+ T cells within CD45+ cells (left), and percentage of CD8+ T cells expressing PD-1, LAG3 or producing IFNγ, TNFα (right) in tumor-bearing WT mice treated as indicated. n = 5 per group. Individual data points with bar denoting mean (g,h,i), representative of two independent experiments (e,f,g,h,i). Scale bar, 2 mm (g). Statistics computed by hypergeometric test with multiple test correction (a)–(d), Log-rank (Mantel-Cox) test (e,f), and one-way ANOVA with Sidak’s multiple comparison (g) or Dunnett’s multiple comparison (h,i).
