%0 Generic
%A Seibel, Tobias Julian
%D 2010
%F heidok:11168
%K immunotherapy , cancer , microenvironment , T lymphocytes
%R 10.11588/heidok.00011168
%T Local Low Dose Irradiation Triggers Tumor Infiltration by Adoptively Transferred and Host T Lymphocytes and Enhances Immunotherapy in Mice
%U https://archiv.ub.uni-heidelberg.de/volltextserver/11168/
%X The use of immunotherapeutic approaches for the treatment of cancer is limited because of the intrinsic resistance of tumors to T cell infiltration and effector function. Enhanced infiltration of T cells can be achieved by inducing an activated tumor microenvironment utilizing whole body irradiation in mice. However, radiotherapy of human cancer with high doses is not applicable in some patients due to complications associated with organ damage. We hypothesized that locally applied low dose irradiation is sufficient to create a niche favoring immune effector cell entry to the tumor.  The RIP1-Tag5 (RT5) transgenic mouse model expressing the simian virus 40 derived T antigen (Tag) as a model tumor antigen was employed for this study. Following in vitro activation, Tag specific T cells derived from donor mice were injected into RT5 mice previously irradiated with doses ranging from 0.5 to 6 Gray. Histological examination demonstrated that transfer of activated tumor-specific CD4 or CD8 posi-tive T cells alone resulted in low T cell frequencies in the tumor tissue, whereas a combination treatment including locally applied low dose irradiation and adoptive transfer of Tag specific T cells boosted tumor infiltration. Reduced tumor hemorrhaging was associated only with the latter treatment and indicated a treatment response. Local enrichment of adoptively transferred activated tumor-specific T cells was found to modulate the tumor microenvironment providing endogenous T cell subsets ac-cess to the tumor tissue. The observed effects correlated with the presence of innate immune cells in the tumor micromilieu which mediated tumor infiltration of T cells by production of nitric oxide (NO). Depletion of this cell population or suppression of NO synthase prevented the treatment effect as indicated by tumor regrowth and increase in mortality.  This is the first demonstration of enhanced influx of immune effector cells triggered by a combination treatment with local low dose irradiation and adoptive T cell transfer that relies on activation of the tumor microenvironment mediated by NO producing innate immune cells. We believe this treatment approach can be a foundation for the development of a novel and promising cancer therapy that utilizes an activated tumor microenvironment to selectively enrich immune effector cells facilitating immune-mediated tumor destruction.