Leveraging innate immunity for GIST therapy

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Project Summary/Abstract While imatinib remains the gold standard for systemic therapy in gastrointestinal stromal tumors (GISTs), the vast majority eventually progress while on treatment and some patients present with resistant tumors. While novel immunotherapies have shown potential in preclinical models, they have yet to demonstrate significant clinical efficacy alone or in combination with tyrosine kinase inhibition. Tumor associated macrophages (TAMs) have been shown to be essential in antitumoral immunity in GIST, and there is evidence that their activation can synergize with imatinib therapy. Dectin-1 is a pattern recognition receptor (PRR) present on TAMs originally described for its ability to stimulate an immune response to fungal pathogens. Activation of dectin-1 on TAMs and dendritic cells (DCs) has been shown to stimulate antitumoral immunity in some preclinical models of solid tumors but there are discrepant results. We found that dectin-1 is highly expressed on TAMs and DCs in a genetically engineered mouse model of GIST, as well as TAMs from human GISTs, regardless of imatinib treatment status. Dectin-1 appears to be largely restricted to M1-like TAMs and DCs, as opposed to tumor cells or other immune cell types. As such, we hypothesize that dectin-1 activation will cause GIST regression via TAMs and DCs and this effect will be augmented by imatinib therapy. Since dectin-1 likely works via immune cells, it will be therapeutic in imatinib-resistant GIST. We will study to role of dectin-1 in the immune response to GIST by performing flow cytometry, RNA seq, and in vitro functional experiments on TAMs and DCs derived from mice treated with vehicle or d-zymosan, a specific dectin-1 agonist. Furthermore, we will isolate TAMs and DCs from mouse and human GISTs and culture them with d-zymosan to determine its direct effects. To determine the anti-tumor efficacy of dectin-1 activation in our mouse model, we will assess tumor size, histology, and KIT signaling after d-zymosan administration. The combination of dectin-1 activation and tyrosine kinase inhibition will be tested in imatinib-sensitive and imatinib-resistant mouse models. The mechanism of dectin-1 activation will be elucidated by depleting TAMs or DCs. The work will take place in the well- established lab of Dr. DeMatteo, a world leader in GIST research, and exemplary surgeon-scientist at the University of Pennsylvania. The fellowship will include immersion in a collaborative and dynamic lab environment, regular seminars, attendance at national conferences, and mentoring of medical and undergraduate students.