For this study, the TCGA urothelial cancer cohort (n = 405) was utilized to determine the relationship between EMT gene signature expression (200 genes) and infiltrating T cell abundance, which was inferred using mRNA expression of 144 T cell genes. A phase II trial of nivolumab in metastatic urothelial cancer (CheckMate 275, n = 212 ) was used to determine the impact of the EMT gene signature (HTG EdgeSeq) and CD8 expression (by immunohistochemistry) on ORR, progression-free (PFS), and overall survival (OS). In the TCGA cohort, the EMT gene signature correlated with infiltrating T cell abundance (CC = 0.60, p < 0.0001). The correlation remained significant after correction for sample purity (CC = 0.37, p < 0.0001) and urothelial cancer molecular subtype (p < 0.0001). In the CheckMate 275 cohort, the EMT gene signature correlated with CD8 expression (CC = 0.29, p < 0.0001), and higher CD8 expression was associated with longer PFS (p = 0.0003) and OS (p = 0.01). There was a significant interaction between the EMT gene signature and CD8 (PFS, p = 0.038; OS, p = 0.064). In tumors with high CD8 expression, ORR, PFS, and OS were worse in high EMT gene signature tumors vs low.
The authors conclude that while much effort has been focused on “turning cold tumors hot” as a strategy to improve the efficacy of PD-1/PD-L1 blockade, a large proportion of “hot tumors” do not respond. Among these, high EMT gene signature tumors are associated with a lower ORR to nivolumab and shorter PFS and OS. These findings substantiate EMT as a potential mechanism of immune escape and raise the possibility of co-targeting EMT and PD-1/PD-L1 in this at-risk subset of urothelial cancers.
Speaker: Matthew D. Galsky, Memorial Sloan Kettering Cancer Center, New York, United States of America
Co-Authors: L. Wang (New York, United States of America) A. Saci (Princeton, United States of America) P. M. Szabo (Princeton, United States of America) Y. Gong (New York, United States of America) J. Zhu (New York, United States of America)
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain
1. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial. Lancet Oncol 2017;18(3):312-322.