Background Although immune checkpoint inhibitor (ICI) approval has changed the treatment landscape of metastatic urothelial carcinoma, approximately 70% of patients succumb to refractory or acquired resistance. Tumor-cell intrinsic upregulation of PPARG is associated with lack of response to anti-PD1 and an immunosuppressive tumor-microenvironment (TME), characterized by anti-inflammatory cytokine signaling, decreased T-cell infiltration, T-cell dysfunction and increased myeloid-derived suppressive cells.
Methods Tumors collected from 1393 patients with muscle-invasive urothelial cancer (MIUC) were sequenced using the Tempus xT assay (DNA-seq of 648 genes at 500x coverage; RNA-seq (1389 patients both, 1365 patients DNA only). Within the dataset, 275 patients received anti-PD1 therapy. Pre-anti-PD1 treatment tissues were analyzed (threshold ≤90 days from start-of-treatment to tissue-collection). PD-L1 expression was assessed using the PD-L1 IHC 22C3 PharmDx assay (Combined Proportion Score [CPS] cut-off of 10%). Gene expression values were normalized by transcripts-per-million (TPM). Immune infiltration was quantified with mcpCounter package in R. Patients were binned in ‘Amplified’ (AMP) vs ‘Non-Amplified’ (non-AMP) groups by PPARG copy-number cut-off of 3. Kaplan-Meier analyses were performed based on real-world Progression Free Survival (rw-PFS) and PPARG amplification.
Results The median mRNA expression level of PPARG was significantly higher in the PPARG AMP group (n= 194) compared to PPARG non-AMP group (n= 1167) (8.81 Log2[TPM+1] vs 7.39 Log2[TPM+1]; p< 2.2e-16). PPARG expression was also higher in the PD-L1-negative tumors (CPS < 10) compared to PDL1-positive tumors (7.79 Log2[TPM+1] vs 7.28 Log2[TPM+1]; p=0.026). PPARG AMP tumors exhibited a cold immune-phenotype compared to the PPARG non-AMP tumors, associated with lower CD8+ T-cell infiltration signature score (3.99 Log2[TPM+1] vs 5.73 Log2[TPM+1]; p=0.0025) and lower expression of other immune cells (table 1). Survival analysis in patients treated with anti-PD1 showed significant shorter rwPFS (p= 0.034) for patients with PPARG AMP (n= 41) compared to the non-AMP group (n= 222).
Conclusions PPARG overexpression and amplification in a large MIUC cohort correlates with low PD-L1 expression, a cold immune-phenotype and lack of response to anti-PD1. Others have demonstrated the significant role PPARG plays in immune modulation of the TME. FX-909, a first-in-class covalent PPARG inverse agonist that will be evaluated in a Ph1 trial this year, will offer an opportunity to investigate the impact of PPARG inhibition on the TME of MIUC patients. FX-909 combination with ICI therapy potentially provides a ‘one-two punch’ strategy to overcome resistance to immunotherapy in MIUC patients with high PPARG expression.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.