V-domain Ig suppressor of T cell activation, VISTA, is a type I transmembrane protein that functions as an immune checkpoint. VISTA can be expressed by a wide range of cell types. Malignant pleural mesothelioma (MPM) is a tumor type with the highest levels of VISTA expression. However, it remains unclear if VISTA could be a predictive or prognostic marker in MPM following PD-1 blockade.
The phase III PROMISE MESO study randomized 144 patients to either chemotherapy (vinorelbine or gemcitabine) or pembrolizumab. We analyzed 62 patients from the pembrolizumab arm and 57 patients from the chemotherapy arm with available tumour tissue. We performed multiplex IHC for the following markers/cell types: calretinin of WT1, CD8, CD14, CD66b, CD11c, VISTA, and DAPI.
Most of the VISTA expression originated from the mesothelioma cells. Bioinformatic analysis of MPM RNAseq data showed enrichment for response to INFa and INFg with VISTA overexpression. Responses to pembro or chemo were not influenced by global VISTA expression. However, VISTA expression on CD66b-positive neutrophils negatively correlated with responses. The VISTA+/CD66b+ median value was 0.56 (IQR: 0.0-3.5), and the rounded median value of 1.0/mm2 was used as threshold. Patients with VISTA+/CD66b+ high had an ORR of 5.6% whereas VISTA+/CD66b+ low tumors had 36.8%. Neutrophil infiltration alone did not correlate with responses. The difference in ORR also translated to prolonged PFS in patients with low VISTA+/CD66b+ cell counts (interaction p=0.0051), but no difference in overall survival was detected (interaction p=0.35). Neutrophils were not predictive of PFS or OS. In public single-cell expression data of lung cancer patients, VISTA expression indeed was higher in a subset of neutrophils, specifically in tN1 and tN3 subtypes.
Overall, our data show that VISTA expressing neutrophils correlate with outcomes. Our data underscore the complex biology of VISTA and suggest that specific targeting of VISTA on neutrophils might be a viable therapeutic option in a subset of MPM patients.
NCT02991482. ETOP 9-15 PROMISE-meso trial.
ETOP IBCSG Partners Foundation.
ETOP IBCSG Partners Foundation, and by Merck Sharpe & Dohme.
All authors have declared no conflicts of interest.