Fig. 5: Inhibition of adenosine signalling diminishes the abundance of Spp1hi-TAMs and enhances the responsiveness of CRPC to PD-1 blockade in vivo.
From: Evolution of myeloid-mediated immunotherapy resistance in prostate cancer
a, Schematic depicting the dosing schedule for ciforadenant (10 mg kg−1) or DMSO in CRPC mice. b, Cumulative CRPC growth after ciforadenant (n = 6) or DMSO (n = 5) treatment, compiled from n = 2 experiments; symbols show mean ± s.e.m. c,d, Quantification of macrophage subset frequency (c) and Spp1hi-TAM numbers (d) in CRPC treated with ciforadenant or DMSO from the same experiments as b; bars show mean + s.e.m.; symbols represent individual mice. e, Heatmap of normalized Adora2a expression (A2AR encoding) in macrophages and monocytes from mouse prostate cancer. f,g, UMAP (f) and bar plots (g) showing AdenoSig scores among myeloid cells in mouse prostate cancer (n = 6,397 myeloid cells; P < 0.001 for Spp1hi-TAM versus other subsets). Boxes denote IQR, and bars denote 25% − 1.5 × IQR and 75% + 1.5 × IQR, with outliers exceeding 1.5 × IQR. The red dashed line shows the median score for Spp1hi-TAMs. h, Schematic of ciforadenant (10 mg kg−1) treatment with and without anti-PD-1 (400 μg) treatment in CRPC mice. i, Cumulative CRPC growth after the treatments in h, compiled from n = 3 experiments; symbols represent mean ± s.e.m. DMSO + isotype, n = 7; DMSO + anti-PD-1, n = 6; ciforadenant + isotype, n = 7; ciforadenant + anti-PD-1, n = 6. j, Density of polyfunctional (IFN-γ+TNF-α+) CD8+ T cells in CRPC after the treatments in h. Each group is represented using the same colour scheme as in i. Bars show mean + s.e.m. from n = 3 experiments; symbols represent individual mice. k, Schematic showing the dosing schedule for ciforadenant (100 mg twice a day for 28 days) with or without atezolizumab (840 mg, once every two weeks) in patients with mCRPC. l, Waterfall plot of maximum prostate-specific antigen (PSA) change from screening in patients treated with ciforadenant either alone (grey) or with atezolizumab (red). m, Computed-tomography images showing tumour reduction in a clinical responder with measurable disease after the combination treatment. Statistical significance was determined by two-sided unpaired Student’s t-tests (b,c), a two-sided Mann–Whitney test (d), a Kruskal–Wallis test with Dunn’s correction (g) and an ordinary one-way ANOVA with Sidak correction (i,j); *P < 0.05, **P < 0.01, ***P < 0.001; NS, not significant.
