Administration-specific migration of Th1 cells modulates the host immune system, tumor microenvironment, and antitumoral efficiency during immunotherapy in pancreatic cancer


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Christoph Griessinger1,Andreas M. Schmid1,Barbara F. Schörg1,Dominik B.A. Krüger1,Daniel Bukala1,Birgit Fehrenbacher2,Ursula Kohlhofer3,Leticia Quintanilla-Martinez3,Martin Schaller2,Martin Röcken2,Bernd J. Pichler1,Manfred Kneilling1
1Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen,2Department of Dermatology, University of Tübingen,3Department of Pathology, University of Tübingen

Abstract

Background

The use of tumor-associated antigen specific Interferon-γ producing CD4+-T helper cells (TAA-Th1) represents a promising alternative for immunotherapies against cancer. We compared the influence of the administration route on the homing of TAA-Th1 cells, the treatment efficiency and the effects on the host immune system in an animal model for pancreatic cancer (RIP1-Tag2).

Method

Therefore, we treated 5-weeks old RIP1-Tag2-mice, which were irradiated initially with 2Gy, weekly intravenously (i.v.) or intraperitoneally (i.p.) with 10e7 Tag2-Th1 cells for 10 weeks. The treatment efficiency was monitored by weekly measurements of the blood glucose level (BGL) and magnetic resonance imaging (MRI). Tag2-Th1 cells, labelled with the fluorescence dye DiD, were administered in week 10 of therapy to monitor their homing patterns by optical imaging. For further ex vivo evaluation we performed H&E-histology, p16/Ki67-immunohistochemistry and flow cytometry of the pancreatic tissue.

Results

Optical imaging of fluorescence-labelled Tag2-Th1 cells revealed administration-specific homing patterns; a strong initial homing to the tumor site could be observed only after i.p.-, but not after i.v.-transfer. Despite these differences, both administration routes induced an equivalent therapeutic effect as demonstrated by MRI, weekly measurements of BGL and histology. Interestingly, the i.v. administration of Tag2-Th1 cells induced senescent p16INK4a-positive/Ki67-negative insular carcinoma cells to a greater extent than i.p. administration. Flow cytometry revealed, that both administration routes of Tag2-Th1 cells induced significant changes in the host immune system; 50% of the host CD4+-population was replenished with Tag2-T cells. Furthermore, both routes induced the recruitment of B cells to the tumors and macrophages were replaced by dendritic cells.

Conclusion

Our results show that both treatment routes induced profound antitumoral effects accompanied by differences in senescence induction and enormous alterations in the host immune system. Thus, especially for the clinical application, administration route-specific effects of Th1 cells must be considered to achieve the greatest therapeutic efficiency.