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Upper Gastrointestinal (lips to ileocecal valve, including esophagus and stomach)

P68: Systemic Treg depletion inhibits tumor growth in gastrointestinal stromal tumor (GIST)

Introduction:


Gastrointestinal stromal tumor (GIST) is the most common human sarcoma. GISTs are often initially sensitive to imatinib or other tyrosine kinase inhibitors, but cure is rare, and resistance often develops. Regulatory T cells (Tregs) are a specialized subpopulation of T cells that promote tumor growth by hindering the effector immune response. Here, we sought to determine the role of intratumoral Tregs in GIST and how they are influenced by imatinib treatment.






Methods:


We used a genetically engineered mouse model harboring a KitV558Δ/+ mutation which results in a single intestinal GIST. These mice were crossed to Foxp3DTR/+ mice, in which the human diphtheria toxin receptor is expressed in Foxp3-expressing cells. Mice (n=3-5/group) were injected i.p. with diphtheria toxin (DT) at 50 ng/ gram body weight or vehicle, and some mice received 4 i.p. doses of anti-CD4 over a week or rat IgG2b isotype antibody. Cytometric bead array was used to measure serum and tumor IFN-γ. Imatinib was used in some experiments at 90 mg/kg/day in the drinking water.






Results:


Intratumoral Tregs were depleted more than 95% 2 days after 1 dose of DT, but recovered by 7 days. Stable depletion of Tregs occurred with 4 doses of DT over 1 week and achieved a 30% reduction in tumor weight vs. control. Tumor reduction depended on CD4 T cells as proven by concomitant CD4 depletion Serum IFN-γ increased 4.25-fold (p< 0.05) and tumor IFN-γ increased 2.5-fold (p< 0.05) vs. control. One week of imatinib treatment alone reduced tumor weight by 42% (p< 0.05) and reduced the frequency of intratumoral Tregs by over 50% (p< 0.05) while Tregs in nearby lymph nodes were unaffected. However, concomitant stable Treg depletion did not further enhance the anti-tumor effect of imatinib.






Conclusions:


Murine GIST is affected by the immune response as Treg depletion reduced tumor size via CD4 T cells and IFN-γ. Imatinib alone reduced intratumoral Tregs. The combination of Treg depletion and imatinib failed to show an additional effect, suggesting an overlap of anti-tumor mechanisms.




Learning Objectives:

  • Upon completion, participant will be able to state the effect of tumor weight reduction after Treg depletion.
  • Upon completion, participant will be able to state the important cell population responsible for the tumor weight reduction.
  • Upon completion, participant will be able to state the effect of combined Treg depletion and Imatinib on tumor weight.