Abstract 4710: Tumor-infiltrating immune cells in gastrointestinal stromal tumors (GIST) related to the response to tyrosine kinase inhibitor therapy
Authors: Hohenberger Peter , Zhao Wenyi , Deligianni Maria , Simon-Keller Katia , Diel Alina , Homburger Andrea , Cao Hui , Marx Alexander 
Published: July 2017

Purpose: The prognostic predictors for neoadjuvant and palliative tyrosine kinase inhibitor (TKI) effect in GIST patients are few beyond mutational status. We analyzed the extent and composition of tumor-infiltrating immune cells in GIST after different TKI therapeutic regimens and response.

Methods: From 60 GIST patients, surgical specimens were available and divided into six different groups of 10 cases each, with the

primary tumors graded for malignant behaviour acc. to Miettinen&Lasota 2006. In the neoadjuvant groups all tumors were biopsy proven and had documented IM-sensitive mutations in the KIT receptor.

- low risk gastric GIST

- high risk GIST of the small bowel

- locally advanced GIST after neoadjuvant imatinib (IM) with &lt;10%

- or &gt;30% of viable cells remaining

- progressive liver metastases resistant to ≥2 TKI inhibitors

- progressive peritoneal mets. resistant to ≥2 TKI inhibitors.

We used 2-μm sections of formalin-fixed, paraffin-embedded tissue samples for immunohistochemistry with the used Dako REAL EnVision Detection System (K5007, Dako) and Anti-CD68 (Dako); Anti-CD11c (Abcam); Anti-CD163 (Leica); Anti-CD11b (Abcam); Anti-CD4 (Leica); Anti-CD8(Leica); Anti-FOXP3 (Abcam) antibodies. The phenotypes of immune cells were compared in the defined GIST groups. Recurrence-free survival (RFS) was evaluated in neoadjuvant and overall-survivals (OS) after TKI failure was measured in TKI resistant M1 patients .

Results: 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. Foxp3+ Tregs, CD163+ M2 macrophages and CD11b+ myeloid cells are significantly higher in TKI resistance or neoadjuvant (viable cells&gt;30%) tissues compared with neoadjuvant (viable cells&lt;10%) cases. 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).

Conclusions: Our study reveals dynamic changes of tumor-infiltrating immune cell protagonists in GISTs after different TKI therapeutic regimen and response. This may help to understand the response to TKI-therapy beyond mutational status and open an option for immunotherapy in patients resistant to standard TKIs.

Citation Format: Peter Hohenberger, Wenyi Zhao, Maria Deligianni, Katia Simon-Keller, Alina Diel, Andrea Homburger, Hui Cao, Alexander Marx. Tumor-infiltrating immune cells in gastrointestinal stromal tumors (GIST) related to the response to tyrosine kinase inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4710. doi:10.1158/1538-7445.AM2017-4710