Combination of chemotherapy and cytokine facilitate adoptive transferred effector T cells homing to the core of metastatic tumors Jiemiao Hu1, Qingnan Zhao1, Xueqing Xia1, Richard Gorlick1, Shulin Li1*, 1Department of Pediatrics-Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA *Corresponding Author
Metastatic disease accounts for most cases of cancer mortality, due to its systemic nature and resistance to existing therapeutics. Immune therapy becomes a viable alternative for treating resistant tumors. In fact, increased immune density in metastasis lesions is associated with beneficial clinical outcomes. 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 upregulates NKG2D ligands on tumor cells in vivo across tumor types and developed a novel CD28 stimulation based approach for fast and persistent 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.
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