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Carcinogenesis. 2019 Apr 29;40(2):289-302. doi: 10.1093/carcin/bgy161.

The administration route of tumor-antigen-specific T-helper cells differentially modulates the tumor microenvironment and senescence.

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Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany.
Department of Dermatology, Eberhard Karls University Tübingen, Tübingen, Germany.
Department of Pathology and Neuropathology, Eberhard Karls University Tübingen, Tübingen, Germany.
Comprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany.
Department of Internal Medicine VIII, University Hospital Tübingen, Tübingen, Germany.
Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, Tübingen, Germany.
Translational Gastrointestinal Oncology Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Immunology, Eberhard Karls University, Tübingen, Germany.
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany.


Cancer treatment with adoptively transferred tumor-associated antigen-specific CD4+ T-helper cells is a promising immunotherapeutic approach. In the pancreatic cancer model RIP-Tag2, the intraperitoneal (i.p.) application of Tag-specific TH1 cells exhibited a profound antitumoral efficiency. We investigated, whether an intravenous (i.v.) application of Tag-TH1 cells induces an equivalent therapeutic effect. Adoptively transferred fluorescent Tag-TH1 cells revealed a pronounced homing to the tumors after either i.p. or i.v. transfer, and both routes induced an almost equivalent therapeutic effect as demonstrated by magnetic resonance imaging, blood glucose level course and histology. The i.v. administration of Tag-TH1 cells induced p16INK4-positive/Ki67-negative tumor senescence more efficiently than i.p. administration. Both routes replenish host CD4+ T cells by transferred T cells and recruitment of B and dendritic cells to the tumors while reducing CD8+ T cells and depleting macrophages. Both administration routes efficiently induced a similar antitumoral efficiency despite the pronounced senescence induction after i.v. administration. Thus, a combinatory i.v./i.p. injection of therapeutic cells might overcome limitations of the individual routes and improve therapeutic efficacy in solid tumors.


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