Abstract 3814: A pan cancer analysis of the tumor inflammation signature
Authors: Patrick Danaher, Sarah Warren, Alessandra Cesano
Journal: Cancer Research (2017)

Abstract Introduction: The Tumor Inflammation Signature (TIS) is an 18 gene signature in development for the detection of adaptive immune response within tumors by measuring expression of genes associated with cytotoxic cells, antigen presentation, and IFNγ activity. The TIS has previously been shown to enrich for a population of patients who respond to the anti-PD1 therapy pembrolizumab. We characterized the behavior of the TIS across a range of tumor gene expression data downloaded from the TCGA in order to understand the distribution of TIS within and between tumor types, with special emphasis on those tumors for which anti-PD1 therapy is approved for use. Methods: The TIS was trained to predict response to pembrolizumab using gene expression profiles from 289 biopsies from 11 different tumor types. Its association with clinical response was retrospectively assessed in an independent set of 200 samples from 14 additional tumor types. We calculated TIS scores in over 9000 samples from 31 TCGA RNASeq datasets. We contrasted TIS with mutational load, with overall survival, and with other gene expression signatures. Results: While TIS scores are higher in classically immunogenic tumor types, they display a significant amount of intersample variability within most tumor types, and a subset of patients can be identified that possess elevated TIS scores consistent with responsiveness to pembrolizumab. TIS genes have highly conserved co-expression patterns across tumor types, consistent with a model in which the genes measure immune-intrinsic transcriptomic activity with minimal contribution of tumor-intrinsic gene expression. Notably, ranking tumors by median TIS score is superior to mutational load ranking at predicting clinical response to anti-PD1. TIS was minimally correlated with mutational load in most tumor types, except in tumor types known for hypermutation-driven by mismatch repair deficiency. TIS and mutation burden had their greatest variability in melanoma; in most other tumors, TIS retains more variability than mutation burden, possibly reflecting patients with anti-tumor immune responses driven by one or a few mutation-derived neoantigens. Average mutation burden and average TIS are positively correlated within most tumor types. Notable exceptions to this trend include two tumors for which anti-PD1 is currently approved. Bladder urothelial carcinoma has lower average TIS than its mutation burden would predict, and kidney renal clear cell carcinoma has much higher average TIS than its mutation burden would predict. Conclusion: The TIS has the potential to enrich for anti-PD1 responders independent of tumor type. It may identify rare potential responders in tumors with low average response rates. These results support further research into the efficacy of anti-PD1 in patients with high TIS scores, regardless of tumor type. Citation Format: Patrick Danaher, Sarah Warren, Alessandra Cesano. A pan cancer analysis of the tumor inflammation signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3814. doi:10.1158/1538-7445.AM2017-3814