Abstract
Preclinical work in murine models suggests that local radiotherapy plus intratumoral syngeneic dendritic cells (DC) injection can mediate immunologic tumor eradication. Radiotherapy affects the immune response to cancer, besides the direct impact on the tumor cells, and other ways to coordinate immune modulation with radiotherapy have been explored. We review here the potential for immune-mediated anticancer activity of radiation on tumors. This can be mediated by differential antigen acquisition and presentation by DC, through changes of lymphocytes’ activation, and changes of tumor susceptibility to immune clearance. Recent work has implemented the combination of external beam radiation therapy (EBRT) with intratumoral injection of DC. This included a pilot study of coordinated intraprostatic, autologous DC injection together with radiation therapy with five HLA-A2(+) subjects with high-risk, localized prostate cancer; the protocol used androgen suppression, EBRT (25 fractions, 45 Gy), DC injections after fractions 5, 15, and 25, and then interstitial radioactive implant. Another was a phase II trial using neo-adjuvant apoptosis-inducing EBRT plus intra-tumoral DC in soft tissue sarcoma, to test if this would increase immune activity toward soft tissue sarcoma associated antigens. In the future, radiation therapy approaches designed to optimize immune stimulation at the level of DC, lymphocytes, tumor and stroma effects could be evaluated specifically in clinical trials.
Highlights
RADIATION EFFECTS A conventional view of radiation is an immune attenuator
Those microenvironment derived molecules include vascular endothelial growth factor (VEGF), tumor growth factor β (TGF-β), reactive oxygen species, the enzyme indoleamine-2,3-deoxygenase, granulocytemacrophage colony stimulating factor (GM-CSF), interleukin-8, interleukin-10. Specific inhibition of these pathways can have a favorable impact on dendritic cell (DC) phenotype and the capacity for meaningful immunologically mediated anticancer response, for example a murine tumor model was induced to be immunologically rejected by use of VEGF depleting antibody (Gabrilovich et al, 1999); a clinical trial using sequential bevacizumab and low dose subcutaneous IL-2 did not demonstrate a significant clinical impact nor impact on DC phenotype for VEGF depletion (Finkelstein et al, 2010)
In further work with the D5 tumor, they found that the loading and presentation of D5-associated antigens by DC was enhanced by D5 irradiation, independent of the low level of tumor cell death that was directly induced by radiation
Summary
OF DC INTO THE TUMOR LOCALE Nikitina and Gabrilovich (2001) initially described the basic model of intratumoral DC injection coordinated with sub-curative irradiation of the primary tumor, in a model system using methA sarcoma (in Balb/C mice) and C3 tumor (in C57BL/6 female mice) tumors. The unmanipulated DC that were placed into irradiated tumor-mediated systemic, lasting antitumor immunity, without any other systemic modulation (Nikitina and Gabrilovich, 2001) In another murine tumor system (C57BL/6 female mice with the D5 tumor, which is a poorly immunogenic subclone the B16-BL6 melanoma, and with the MCA205 fibrosarcoma), TeitzTennenbaum et al (2003) observed superior survival in mice treated with a combined radiation and intratumoral DC injection protocol. Further they found that loading of the DC with antigen in situ was superior to ex vivo loading with irradiated tumor lysate. Assays for several inflammatory cytokines (using cultures of tumor cells), including IL-12p70, TNF-α, IFN-γ, IL-6, and IL-10 did not show changes following the tumor irradiation, and tumor-specific CD8+ T cells did not accumulate in the tumor (Teitz-Tennenbaum et al, 2008)
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