Fig. 1: Chronic IFNγ exposure drives resistance to α-PD-1 therapy and upregulates PARP14.

A YUMM2.1, CT26, and MC38 cells were implanted into 8–12-week-old wild-type syngeneic female mice after two-weeks pre-treatment with IFNγ (50 IU/mL) or BSA. Treatment with the control IgG2a or α-PD-1 antibody was initiated once tumour volume reached 80–100 mm³, with dosing every three days for a total of four doses. B–D Average tumour growth curve for B YUMM2.1 (BSA: n = 3; IFNγ: n = 3), C CT26 (BSA: n = 6; IFNγ: n = 6), and D MC38 (BSA: n = 5; IFNγ: n = 6) cells after initiating treatment with the control IgG2a antibody. Number of mice treated indicated in parentheses. The p-value for tumour growth was assessed for the last day of IgG2a treatment and were determined by an unpaired two-sided t-test with Welch’s correction. The data were presented as the mean ± SEM. E–G The growth curve of each E YUMM2.1 (n = 6), F CT26 (n = 4), and G MC38 (n = 8) tumour pre-treated with BSA receiving α-PD-1 therapy. H–J The growth curve of each H YUMM2.1 (n = 6), I CT26 (n = 4), and J MC38 (n = 8) tumour pre-treated with IFNγ receiving α-PD-1 therapy. K Gene expression heatmap of differentially expressed genes (complete Euclidean HCL clustered; log2 fold change ≥ ±0.5; FDR ≤ 0.1) in mouse (B16-F10, YUMM2.1, MC38, 5555) or human (A375, 501-Mel,) tumour cell lines treated with chronic IFNγ (50 IU/mL for mouse and 20 IU/mL for human) compared to BSA treatment. Three independent cell line samples were sequenced for both conditions and the average for each cell line is shown. Heatmap also includes differential gene expression comparing melanoma patient samples with the 15% highest IFNG expression level with the 15% lowest (data retrieved from TCGA SKCM RNA sequencing data using Broad GDAC Firehose). Source data are provided as a Source Data file.