Fig. 3: TME reshaping with radioimmunotherapy in immune cold tumors.
a, Bar plot of the 10 most upregulated gene sets from baseline to 3–6 weeks on therapy in TMB-low tumors in the SBRT (n = 12 samples) and control (n = 11 samples) arms, including neutrophil degranulation (FDR-adjusted P = 4.93 × 10−30 in the SBRT arm and P = 1.58 × 10−9 in the control arm), IFNγ response (FDR-adjusted P = 1.69 × 10−12 in the SBRT arm and P = 5.97 × 10−12 in the control arm), chemokine signaling (FDR-adjusted P = 7.94 × 10−11 in the SBRT arm and P = 9.79 × 10−6 in the control arm), overall inflammatory response (FDR-adjusted P = 1.12 × 10−9 in the SBRT arm and P = 2.68 × 10−7 in the control arm), and antigen processing and presentation (FDR-adjusted P = 5.40 × 10−8 in the SBRT arm and P = 1.92 × 10−5 in the control arm). Extensive findings can be found in Supplementary Table 16. b, Bar plot of the 10 most upregulated gene sets from baseline to 3–6 weeks on therapy in PDL1-null tumors in the SBRT (n = 9 samples) and control (n = 9 samples) arms, including IFNγ response (FDR-adjusted P = 3.94 × 10−34 in the SBRT arm and P = 5.52 × 10−6 in the control arm), IFNα response (FDR-adjusted P = 1.29 × 10−17 in the SBRT arm and P = 1.08 × 10−2 in the control arm), NK cell cytotoxicity (FDR-adjusted P = 3.28 × 10−16 in the SBRT arm and P = 6.43 × 10−6 in the control arm), BCR signaling (FDR-adjusted P = 6.47 × 10−15 in the SBRT arm and P = 0.84 in the control arm), and antigen processing and presentation (FDR-adjusted P = 1.15 × 10−14 in the SBRT arm and P = 3.73 × 10−5 in the control arm). Extensive findings can be found in Supplementary Table 16. c–e, Heat map of GSEAs showing the most upregulated immune gene sets from baseline to 3–6 weeks on therapy in TMB-high tumors in the SBRT arm (n = 4 samples), TMB-low tumors in the SBRT arm (n = 11 samples) and TMB-low tumors in the control arm (n = 10 samples) (c), in PDL1-positive tumors in the SBRT arm (n = 6 samples), PDL1-null tumors in the SBRT arm (n = 8 samples), PDL1-positive tumors in the control arm (n = 4 samples) and PDL1-null tumors in the control arm (n = 8 samples) (d), and in Wnt wild-type tumors in the SBRT arm (n = 12 samples), Wnt-mutated tumors in the SBRT arm (n = 2 samples) and Wnt wild-type tumors in the control arm (n = 10 samples) (e). Each row represents a gene set; gene sets are grouped into nine categories shown in the legend. Enrichment scores were normalized by row to a maximum value of 1. For every cohort stratification (TMB-high versus TMB-low, PDL1-positive versus PDL1-null and Wnt-mutated versus Wnt wild-type tumors), we observed greater enrichment of immune gene sets in the SBRT arm than the control arm across a broad range of immune gene sets. f, Enrichment plot of the IFNγ gene set in on-therapy tumors with low TMB in the SBRT arm (n = 12 samples; FDR-adjusted P = 1.69 × 10−12). g, Enrichment plot of the IFNγ gene set in on-therapy PDL1-null tumors in the SBRT arm (n = 9 samples; FDR-adjusted P = 3.94 × 10−34). h, Enrichment plot of the IFNγ gene set in on-therapy Wnt-mutated tumors in the SBRT arm (n = 5 samples) from baseline to 3–6 weeks on therapy (FDR-adjusted P = 4.78 × 10−13). All statistical results are two-sided P values. Dotted black horizontal lines indicate FDR-adjusted P = 0.05.
