Background: Tumor Inflammation signatures (TIS) comprising multiple immune genes have been shown to enrich for response to ICI. To study this immune phenotype in a large cohort of clinically evaluated patients, we studied gene expression data for a stable pan-cancer tumor inflammation profile and clinical response to ICI. Methods: 1323 FFPE tumors from 35 histologies were tested by RNA-seq, PD-L1 IHC and DNA-seq for TMB. Unsupervised analysis of the RNA-seq data revealed a cluster of 160 genes which separated inflamed from non-inflamed tumor microenvironments (TME). A TIS, algorithmically defined as the mean mRNA expression of the 160 genes was developed with each tumor assigned into a weak, moderate or strong inflammation group. PD-L1 IHC was performed using DAKO 22C3 antibody and considered positive if TPS ≥1%. TMB > 10 mut/Mb was considered high. The TIS, PD-L1 and TMB were independently applied to 110 NSCLC cases for association with ORR to ICIs by RECIST criterion. Results: Unsupervised clustering identified 3 inflammation clusters in the 1323 samples; inflamed (n = 439; 33.2%), borderline (n = 467; 35.3%) and non-inflamed (n = 417; 31.5%). 160 genes are over-represented by T & B-cell activation, IFNg, chemokine, cytokine and interleukin pathways. The TIS algorithm results in an inflammatory score that leads to 3 distinct groups of strong (n = 384; 29.0%), moderate (n = 354; 26.8%) and weak (n = 585; 44.2%) inflammation. Strongly inflamed tumors are over-represented by PD-L1+ tumors (240/384) whereas weakly inflamed tumors are significantly under-represented by PD-L1+ tumors (369/585; p = 1.02e-14). Strongly inflamed tumors presented with improved ORR to ICI in NSCLC (36.6%; 16/44; p = 0.051). Similar results were observed for overall survival for strongly inflamed tumors (median = 16 months; p = 0.0012) vs. weakly inflamed tumors (median = 8 months). ORR for PD-L1+ 33.96% (p = 0.026) and TMB high 21.43% (p = 0.83) were observed. Conclusions: Concurrent measurement of multiple markers led to a comprehensive, stable TIS that predicts host immune response. A strongly inflamed TIS was associated with higher ORR versus single biomarker PD-L1 and TMB in NSCLC.