Sarcoma
CME
Katherine J. Tardy, MD
Post-Doctoral Research Fellow
University of Pennsylvania, United States
Disclosure(s): No financial relationships to disclose
Katherine J. Tardy, MD
Post-Doctoral Research Fellow
University of Pennsylvania, United States
Disclosure(s): No financial relationships to disclose
Andrew Tieniber, MD
General Surgery Resident
University of Pennsylvania
phialdelphia, Pennsylvania, United States
Disclosure information not submitted.
Hyunjee V. Kwak, MD
Postdoctoral Research Fellow
University of Pennsylvania, United States
Disclosure(s): No financial relationships to disclose
Kevin Do, BS
Laboratory Technician
University of Pennsylvania, United States
Disclosure information not submitted.
Laura Wang, BS
Laboratory Technician
University of Pennsylvania, United States
Disclosure information not submitted.
Shan Zeng, PhD
Senior Scientist
University of Pennsylvania, United States
Disclosure information not submitted.
Ferdinando Rossi, PhD
Senior Scientist
University of Pennsylvania, United States
Disclosure information not submitted.
Ronald P. DeMatteo, MD, FACS (he/him/his)
Chair, Department of Surgery
The Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States
Disclosure information not submitted.
GIST is the most common human sarcoma, and 90% of tumors are attributable to a mutation in KIT or PDGFRA. The tyrosine kinase inhibitor Imatinib is not curative as most patients will develop resistance, and its efficacy is influenced by the tumor microenvironment. ICOS is an immune inhibitory protein found on T cell subsets particularly anti-inflammatory IL-10 producing regulatory T cells (Tregs). We sought to target ICOS to improve imatinib’s effects.
Methods:
Bulk and single-cell RNA sequencing and flow cytometry were performed to identify cell types expressing ICOS and its ligand ICOSLG in KitV558Δ/+ mice, which develop intestinal GISTs. A blocking ICOS antibody, isotype control, imatinib, or combination therapy was administered i.p. for 1 or 2 weeks to KitV558Δ/+ mice. Flow cytometry and analysis of tumor characteristics such as tumor weight and cellularity by IHC were performed to investigate the effects of ICOS antagonism.
Results:
Single-cell RNA sequencing revealed that ICOS is expressed primarily by T cells and basophils, while ICOSLG is expressed primarily by cells of myeloid origin. Bulk RNA sequencing showed that 3 weeks of imatinib in KitV558Δ/+ mice increased tumor ICOS expression. Flow cytometry showed that 1 week of imatinib therapy increased ICOS surface protein expression in regulatory T cells to 79% from 60% in untreated controls (n=5 per group). ICOS inhibition did not decrease the overall percentage of Treg cells. However, most (89.5%) IL-10+ Tregs also expressed ICOS, and anti-ICOS therapy decreased these IL-10 producing Treg cells specifically. Anti-ICOS also increased intratumoral CD8+ T cells and decreased CD4+ T cells (p < 0.05). Combination therapy with imatinib increased dendritic cells and monocytes while decreasing CD8+ T cells and macrophages (p < 0.05). ICOS inhibition alone did not decrease tumor weight significantly as compared to untreated control, but combination therapy decreased tumor weight by nearly 66% more than imatinib alone and noticeably decreased cellularity on H&E as compared to imatinib therapy.
Conclusions:
ICOS blockade increased the antitumoral effect of imatinib in a genetically engineered mouse model of GIST. ICOS is a new potential target for immunotherapy against human GIST.