The presence of tumor infiltrating lymphocytes has been associated with a higher objective response rate (ORR) to PD-1/PD-L1 blockade. Across a variety of cancers, high EMT gene expression correlates with increased T cell infiltration. The impact of these interrelated processes on outcomes with PD-1/PD-L1 blockade has not been defined.
The TCGA UC cohort (n = 405) was utilized to determine the relationship between EMT gene signature (sig) expression (200 genes in MSigDB) and infiltrating T cell abundance (ITA). ITA was inferred using mRNA expression of 144 T cell genes. A phase 2 trial of nivo in metastatic UC (CheckMate 275, n = 212) was used to determine the impact of EMT sig (HTG EdgeSeq) and CD8 expression (IHC) on ORR, progression-free (PFS), and overall survival (OS).
In the TCGA cohort, EMT sig correlated with ITA (CC = 0.60, p
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 “hot” UC, EMThigh tumors are associated with a lower ORR to nivo 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 “hot” UC.
Clinical trial identification
Legal entity responsible for the study
M.D. Galsky: Received research funding from Bristol-Myers Squib, Novartis, and Merck and has served on advisory boards for Genentech, Merck, EMD-Serono and AstraZeneca. A. Saci and P.M. Szabo: Employees of Bristol-Myers Squib. All other authors have declared no conflicts of interest.