Analysis of tumor-infiltrating immune cells in gastrointestinal stromal tumors (GIST) after tyrosine kinase inhibitor therapy.

Abstract

11042 Background: There is initial evidence that immune-infiltrates of tumor may correlate with the clinical course of patients with GIST beyond the response to tyrosine kinase inhibitors (TKI) according to the mutational status. We were interested to analyze the composition of tumor-infiltrating immune cells in GIST tumor tissues after different TKI regimens vs untreated controls. Methods: From 40 GIST patients who were treated with imatinib alone (neoadjuvant group) and other TKIs (M1 HEP group, progressing on more than ≥2 TKI inhibitors) prior to tumor removal, surgical specimens were available at ten 10 cases each,. They were compared with 20 untreated primary tumors graded for malignant behaviour (low vs high risk ) acc. to Miettinen&Lasota 2006. 2-μm sections of formalin-fixed, paraffin-embedded tissue samples were used for IHC-staining anti-CD68 (Dako); anti-CD11c, anti-CD11b, anti-FOXP3 (all Abcam); anti-CD163, anti-CD4 , anti-CD8 (all Leica). Evaluation was performed with Dako REAL EnVision Detection System (K5007). The phenotypes of immune cells were compared in the defined GIST groups. In the neoadjuvant group we used recurrence-free survival (RFS) for correlation, and overall survival (OS) after TKI failure in the M1 HEP group. Results: Foxp3+ Tregs, CD163+ M2 macrophages and CD11b+ myeloid cells are significantly higher in TKI resistance or neoadjuvant (viable cells > 30%) tissues compared with neoadjuvant (viable cells < 10%) cases. The rate of CD11c+ M1 macrophages is higher in low-risk GISTs compared to high risk GISTs, but CD11b+ myeloid cells are exactly the opposite. Kaplan-Meier curves show high CD163+ M2 macrophages or CD11b+ myeloid cells to correlate significantly with worse RFS in after neoadjuvant IM (p 0.01). In the TKI resistant condition, patients with high CD11c+ M1 macrophages show better median OS (p = 0.07, ns). Conclusions: Our study reveals dynamic changes of tumor-infiltrating immune cell protagonists in GISTs after different TKI therapeutic regimen and after neoadjuvant treatment. We could not detect a different immune infiltrate in untreated primary tumors of different risk categories.