(P 239) CHARACTERIZING THE ROLES OF T-CELLS IN THE CONTEXT OF TUMOR CLEARANCE AND MEMORY IN THE KP MODEL OF SARCOMA FOLLOWING STING THERAPY

Objective: Recent studies have shown that the stimulator of interferon genes (STING) agonist, E7766 can induce tumor clearance in the murine KP model of soft tissue sarcoma (STS). Following STING therapy with this translational STING agonist, tumor infiltrating lymphocyte frequencies increase. As lymphocytes are dominant mediators of tumor cell killing, we sought to investigate the contributions of CD4+ and CD8+ lymphocytes in the context of tumor clearance and subsequent protection against a model of STS recurrence.

Methods: C57BL/6 mice bearing STS tumors were treated intratumorally with a single dose of E7766 and were followed for survival in control and CD8+T-cell depleted states. Following survival studies, mice that showed evidence of STS eradication for over 90 days were re-challenged with an inoculation of STS cells in the contralateral limb. Re-challenged mice were allocated into control, anti-CD8+ and anti-CD4+ antibody depletion groups. Depletion was confirmed via flow cytometry.

Results: In a CD8+ depleted state, the therapeutic benefit of E7766 therapy was entirely negated, while non-depleted controls exhibit tumor clearance frequencies of 38%. Following contralateral limb re-challenge, 88% of E7766 surviving mice retained protection against STS. In a CD8+ T-cells depleted state, 100% of survivors continued to demonstrate immunity against STS re-challenge. However, in a CD4+ T-cell depleted state, 60% of mice developed STS tumors following re-challenge.

Conclusion: Following treatment with the translational STING agonist E7766, STS tumor clearance is primarily dependent on CD8+ T-cells. However, the adaptive immune protection conferred following STING therapy following re-challenge appears to be largely CD4+ T-cell dependent. Further characterization of the immunologic landscapes of relapsed tumors following re-challenge are ongoing. Ultimately, the characterization of the immunologic landscapes of STS tumors, particularly the lymphocyte populations will be critical for further understanding of responsiveness of tumors to therapy and long term protection against disease recurrence.