Dataset Information

Association between the exposure to anti-angiogenic agents and tumour immune microenvironment in advanced gastrointestinal stromal tumours.

ABSTRACT:

Background

Tumour immune microenvironment (TIME) of gastrointestinal stromal tumours (GISTs) is largely unknown.

Methods

A total of 81 surgical specimens from 67 patients with advanced GISTs were categorised into treatment groups: tyrosine kinase inhibitor (TKI)-naive, n = 20; imatinib-progressed and no exposure to sunitinib or regorafenib (IM-PD), n = 30; and imatinib-progressed and sunitinib and/or regorafenib-treated (IM-PD/SU-treated), n = 31. Multiplexed immunofluorescence staining and RNA sequencing were performed to define TIME.

Results

PD-L1 expression rate (>1%) of DOG-1⁺ tumour cells was 5.0, 6.7, and 29.0% in TKI-naive, IM-PD, and IM-PD/SU-treated group, respectively (p = 0.02). FoxP3 expression of CD3⁺ T cells and CD204⁺ CD68⁺ monocytes per DOG-1⁺ cells was significantly higher in IM-PD/SU-treated group compared to TKI-naive and IM-PD groups (p < 0.05). IM-PD/SU-treated group showed increased expression of PD-1 on CD3⁺ T cells (p = 0.03 vs TKI-naive; p = 0.003 vs IM-PD) and DOG-1⁺ tumour cells (p = 0^.02 vs TKI-naive; p = 0.006 vs IM-PD), TIM-3 expression on CD3⁺ T cells (p = 0.01 vs TKI-naive; p = 0.002 vs IM-PD), and LAG3 expression on CD3⁺ T cells (p = 0.001 vs TKI-naive; p = 0.004 vs IM-PD). In the RNAseq analysis, TIGIT expression was significantly increased in IM-PD/SU-treated GISTs compared to IM-PD (p = 0.01).

Conclusion

Immunosuppressive phenotype was predominant in tumours treated with anti-angiogenic agents compared to TKI-naive and IM-treated tumours.

SUBMITTER: Yoo C

PROVIDER: S-EPMC6888806 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundPatients with advanced gastrointestinal stromal tumours (GISTs) resistant to the tyrosine kinase inhibitors imatinib and sunitinib may be treated with regorafenib, which resulted in a median progression-free survival (PFS) of 4.8 months in the GRID trial. Also, pazopanib, another tyrosine kinase inhibitor, has been studied in a randomized, placebo-controlled trial (PAZOGIST) in the third line, which showed a PFS of 45.2% 4 months after study entry, but patients intolerant to sunitinib were also included. We designed another trial evaluating pazopanib, enrolling only patients with progression on both imatinib and sunitinib.Patients and methodsSince all eligible patients had progressive disease, we preferred a non-randomized, phase II multicentre trial so that all patients could receive a potentially active drug. Patients had a progressive metastatic or locally advanced GIST and were ≥18 years of age, with a performance status of 0-2, and sufficient organ functions. The primary endpoint was disease control rate (defined as complete remission + partial remission + stable disease) at 12 weeks on pazopanib. A Simon's two-stage analysis was used with an interim analysis 12 weeks after enrollment of the first 22 patients, and if passed, there was a full enrolment of 72 patients. GIST mutational analysis was done, and most patients had pazopanib plasma concentration measured after 12 weeks.ResultsSeventy-two patients were enrolled. The disease control rate after 12 weeks was 44%, and the median PFS was 19.6 weeks (95% confidence interval 12.6-23.4 weeks). Pazopanib-related toxicity was moderate and manageable. No statistically significant differences were found related to mutations. Plasma concentrations of pazopanib had a formal but weak correlation with outcome.ConclusionPazopanib given in the third line to patients with GIST progressing on both imatinib and sunitinib was beneficial for about half of the patients. The PAGIST trial confirms the results from the PAZOGIST trial, and the median PFS achieved seems comparable to the PFS achieved with regorafenib in the third-line setting.