Abstract
BackgroundThe 18-gene tumor inflammation signature (TIS) is a clinical research assay that enriches for clinical benefit to immune checkpoint blockade. We evaluated its ability to predict clinical benefit of immunotherapy in cancer patients treated with PD-1 checkpoint inhibitors in routine clinical care.MethodsThe CERTIM cohort is a prospective cohort which includes patients receiving immune checkpoint inhibitors in Cochin University hospital. RNA extracted from 58 archival formalin fixed paraffin embedded tumor blocks (including 38 lung cancers, 5 melanomas, 10 renal carcinomas, 4 urothelial carcinomas and 1 colon carcinoma) was hybridized to a beta version of the NanoString® PanCancer IO360™ CodeSet using nCounter® technology. Gene expression signatures were correlated with tumor responses (by RECIST criteria) and overall survival. PD-L1 immunostaining on tumor cells was assessed in 37 non-small cell lung cancer (NSCLC) samples and tumor mutational burden (TMB) measured by whole exome sequencing in 19 of these.ResultsTIS scores were significantly associated with complete or partial response to anti-PD-1 treatment in the whole cohort (odds ratio = 2.64, 95% CI [1.4; 6.0], p = 0.008), as well as in the NSCLC population (odds ratio = 3.27, 95% CI [1.2; 11.6], p = 0.03). Patients whose tumor had a high TIS score (upper tertile) showed prolonged overall survival compared to patients whose tumor had lower TIS scores, both in the whole cohort (hazard ratio = 0.37, 95% CI [0.18, 0.76], p = 0.005) and in the NSCLC population (hazard ratio = 0.36, 95% CI [0.14, 0.90], p = 0.02). In the latter, the TIS score was independent from either PD-L1 staining on tumor cells (spearman coefficient 0.2) and TMB (spearman coefficient − 0.2).ConclusionsThese results indicate that validated gene expression assay measuring the level of tumor microenvironment inflammation such as TIS, are accurate and independent predictive biomarkers and can be easily implemented in the clinical practice.
Highlights
The 18-gene tumor inflammation signature (TIS) is a clinical research assay that enriches for clinical benefit to immune checkpoint blockade
Several genes showed a differential expression in responders to anti-PD-1 [patients with complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria] compared to non-responders (Additional file 1: Table S1)
A high TIS score was significantly associated with response to anti-PD-1 treatment (Fig. 1b)
Summary
The 18-gene tumor inflammation signature (TIS) is a clinical research assay that enriches for clinical benefit to immune checkpoint blockade. Immune checkpoint inhibitors (ICI), blockade of the PD-1/PD-L1 pathway via monoclonal antibodies, have entered the oncology therapeutic arsenal and are being evaluated in an increasing number of indications, the response rates as single agents and in unselected patient populations are usually low. As ICI disrupt pathways that are conserved between tumor cells from multiple different tumor types and the immune environment, biomarkers which are predictive across a variety of indications are of particular interest. An 18 gene “tumor inflammation signature” (TIS) which quantifies an activated but suppressed adaptive immune response in the tumor microenvironment, was demonstrated to retrospectively predict clinical benefit of anti-PD-1 in various cancer types (melanoma, head and neck squamous cell carcinomas, digestive cancers, ovarian and triple negative breast cancers) in clinical trials [2]. The signature has been analytically validated [8, 9] and is currently under investigation in multiple Research Use Only (RUO) and Investigational Use Only (IUO) studies for performance as a predictive biomarker
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