Tumor IFN signaling is associated with the expression of multiple T-cell ligands, myeloid cell signatures, and driver mutations. The NCRCCI-DLBCL data set contains 562 patients, with 475 patients with matched RNA-sequencing and DNA somatic variants data, and survival data for 231 patients treated with R-CHOP–like immunochemotherapy. The ISG.RS signature score was calculated for each patient, and a median score cutoff for the 562 patients was determined to separate ISG.RS high and ISG.RS low groups. (A) Association of ISG.RS with selected T-cell ligands. Top: gene expression of T-cell ligand genes in patients with ISG.RS high. Bottom: ISG.RS low. Included are CD274/PD-L1, PDCD1LG2/PD-L2, CD80/B7-1, CD86/B7-2, HHLA2, LGALS9/Galectin-9, C10orf54/VISTA, and PVR/CD155. (B) Comparison of the median expression of T-cell ligands between ISG.RS high and ISG.RS low. (C) Unbiased clustering of ISG.RS scores with myeloid cell type scores determined by gene set variation analysis. (D) Overall survival of 231 patients treated with R-CHOP stratified according to ISG.RS high vs low. Left: overall survival using the median cutoff as in panels A and B. Right: overall survival using an optimal cutoff (survminer R package). P value by log-rank test. (E) Association of ISG.RS scores with driver mutations. Left: comparison between SOCS1 wild-type (WT) and mutant patients according to ISG.RS score. Right: comparison between KLHL6 WT and mutant according to ISG.RS score. ****P < .0001.