Treatment with doxorubicin and PD-1/CTLA-4 blockade improves T cell activation and anti-tumor efficacy in MCA-205 murine fibrosarcoma

Abstract Immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 produce responses in about 20% of adult soft tissue sarcomas (STSs), however, most patients do not respond, potentially from poor T cell activation. Standard chemotherapy for STSs includes the anthracycline doxorubicin (DOX) which has been shown preclinical cancer models to induce immunogenic death (ICD) via tumor production type I interferons (IFN). We hypothesized that induction ICD IFN release by would enhance activation, infiltration, boost anti-tumor efficacy when combined with dual anti-PD-1/CTLA-4 blockade MCA-205 murine fibrosarcoma model. tumors were generated C57BL/6 mice treated DOX, anti-PD1 (RMP1–14), anti-CTLA4 (9D9 mouse IgG2b) or a surrogate botensilimab, an IgG2b.DLE) antibody enhanced binding FcγR, combination DOX plus anti-PD-1/CTLA-4. found reduction growth improved survival (median reached) DOX/PD-1/CTLA-4 compared 29.5 days). This correlated 2-fold increased influx TILs as measured flow cytometry immunohistochemistry, marked increase CD8:CD4 ratio expression activation markers (PD-1, 4–1BB TIM3). TCR Vβ clonotyping revealed shift clonotype frequency relative other treatment groups. Pathway analysis bulk RNA sequencing demonstrated upregulation control tumors. Further work will correlate these findings human STS receiving CTLA-4/PD-1 ongoing clinical trial (NCT04028063). was supported grants University Colorado Cancer Center (P30CA046934) School Medicine.