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

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.