Abstract 2626: Combination of chemotherapy and cytokine facilitates adoptive transferred effector T cells homing to the core of metastatic tumors

Abstract

Abstract Metastatic disease accounts for most cases of cancer mortality, due to its systemic nature and resistance to existing therapeutics for primary tumors. Immune therapy has become a viable alternative for treating drug-resistant tumors. In fact, increased immune density in metastasis lesions is associated with beneficial clinical outcomes. Notably, tumor infiltrating lymphocyte (TIL) infusions extended the overall survival of refractory melanoma patients. However, whether or not T cell therapy could be used to successfully limit the metastatic progression largely depends on the complexity of T cell penetration and tumor-immune cell interaction in distant sites. During the past years, our group has identified a simple combination of an immune stimulatory signal (interleukin-12) and chemotherapy (doxorubicin) that persistently induces NKG2D ligand on tumor cells in vivo across tumor types and developed a novel CD28 stimulation based approach for fast induction of NKG2D receptor on CD8+ T cells. We found in breast carcinoma model (4T-1) and pediatric osteosarcoma models (K7M3 and LM8), adoptive transfer of NKG2D+CD8+ T cells after the combination of IL-12 plus doxorubicin treatment dramatically reduced the numbers and sizes of metastatic nodules, leading to significantly prolonged survival time. Mechanically, the treatment of IL-12 plus doxorubicin widely upregulated the expression of NKG2D ligands exclusively on tumor cells in metastatic lesions, and allowed high density of NKG2D+CD8+ T cell accumulation at both the core and invasive margin areas of metastatic tumors. Furthermore, this combination therapeutic led to reduced regulatory T cell infiltration, resulting in increased CD8+ T cell to regulatory T cell ratios in metastatic tumors. Collectively, here we reported that a simple combination treatment of IL-12 plus doxorubicin with subsequent NKG2D+ CD8+T cell adoptive transfer may transform the metastatic tumor microenvironment to enable the influx of NKG2D+CD8+ T cells which effectively kill tumor cells via NKG2D-NKG2D ligand interaction. This promising therapeutic approach greatly improved the effectiveness and potential of adoptive T cell therapy in treating cancer patients with metastatic diseases. Citation Format: Jiemiao Hu, Qingnan Zhao, Xueqing Xia, Richard Gorlick, Shulin Li. Combination of chemotherapy and cytokine facilitates adoptive transferred effector T cells homing to the core of metastatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2626.