Ficacy of PDT-induced anti-tumor immunity relies both on innate and humoral immunity, and is a significant determinant of the overall outcome following photofrin-PDT [175]. Finally, BPD-PDT of poorly immunogenic mouse sarcomas (RIF1) in immunocompetent C3H/HeN mice led to the disappearance of tumors followed by an eventual recurrence. The authors then transfected the RIF-1 tumors with green fluorescent protein (GFP) of jellyfish origin, hypothesizing that tumors bearing a foreign protein would subsequently increase the tumors’ visibility to the host’s immune system. Indeed, BPD-PDT of the GFP transfected RIF1 tumorshttp://www.thno.orgTheranostics 2016, Vol. 6, Issueled to a 100 cure rate, suggesting that the GFP served as an immune sensitizing antigen that promoted sustained anti-tumor activity by the host immune system [176]. The ability of PDT to induce systemic anti-tumor immunity via tumor cell death and subsequent immune sensitization has led to several studies exploring the development of PDT generated anti-tumor vaccines. This technique is based on the generation and injection of tumor cell lysates following PDT ex vivo. Several studies demonstrated a robust anti-tumor immunity following immunization with PDT treated tumor cells, including EMT6 cells (human mammary sarcoma), P815 cells (mouse mastocytoma), and SCCVII cells (mouse squamous cell Necrosulfonamide price carcinoma) [157, 177, 178]. The mechanism underlying antitumor immunity likely relies heavily on DAMP release following PDT-induced cytotoxicity. Importantly, cells treated with Ultra-violet (UV) or ionizing radiation do not induce tumor immunization to the same extent as PDT, demonstrating the specificity of PDT in sensitizing immune cells to untreated tumor cells situated in deep tissue [157]. In addition to a PDT-induced systemic immune response, the impact of PDT on the microvasculature of pathologic tissues also has potential to induce therapeutic effects in deep tissue. PDT-induced endothelial damage leads to vessel contraction, vascular leakage, and basement membrane exposure [179]. In addition to serving as a potent signal for platelet aggregation via the coagulation cascade, basement membrane exposure leads to thromboxane release as well as complement cascade activation, thereby contributing to the acute inflammatory effects of PDT described above. The destructive effects of PDT on the vasculature, termed microvessel shutdown, have been exploited in therapeutic applications as a way to induce hypoxia in tumor or diseased tissue [180, 181]. The mechanism underlying PDT-induced microvessel shutdown may involve PDT based inhibition of nitric oxide (NO) release, a vasodilatory molecule, leading to local hypoxia. A study by Korebelik et al. suggested that PDT-induced inhibition of NO led to enhanced cure rates in endogenous NO producing tumors, indicating that the beneficial effects of PDT-induced vascular shutdown can be abrogated with vasodilation. In addition, tumors with low endogenous production of NO were more sensitive to Photofrin-PDT, and addition of NO inhibitors did not improve outcomes [182]. Local hypoxia at the target site coupled with PDT-induced oxidative stress to microvasculature via superoxide anion formation creates an area of tissue ischemia, which serves as a potent stimulator ofcomplement activation and neutrophil infiltration, further enhancing the PDT-induced innate immune AZD3759 custom synthesis response in addition to creating areas of hypoxia at depth [176, 182]. The mechanistic be.Ficacy of PDT-induced anti-tumor immunity relies both on innate and humoral immunity, and is a significant determinant of the overall outcome following photofrin-PDT [175]. Finally, BPD-PDT of poorly immunogenic mouse sarcomas (RIF1) in immunocompetent C3H/HeN mice led to the disappearance of tumors followed by an eventual recurrence. The authors then transfected the RIF-1 tumors with green fluorescent protein (GFP) of jellyfish origin, hypothesizing that tumors bearing a foreign protein would subsequently increase the tumors’ visibility to the host’s immune system. Indeed, BPD-PDT of the GFP transfected RIF1 tumorshttp://www.thno.orgTheranostics 2016, Vol. 6, Issueled to a 100 cure rate, suggesting that the GFP served as an immune sensitizing antigen that promoted sustained anti-tumor activity by the host immune system [176]. The ability of PDT to induce systemic anti-tumor immunity via tumor cell death and subsequent immune sensitization has led to several studies exploring the development of PDT generated anti-tumor vaccines. This technique is based on the generation and injection of tumor cell lysates following PDT ex vivo. Several studies demonstrated a robust anti-tumor immunity following immunization with PDT treated tumor cells, including EMT6 cells (human mammary sarcoma), P815 cells (mouse mastocytoma), and SCCVII cells (mouse squamous cell carcinoma) [157, 177, 178]. The mechanism underlying antitumor immunity likely relies heavily on DAMP release following PDT-induced cytotoxicity. Importantly, cells treated with Ultra-violet (UV) or ionizing radiation do not induce tumor immunization to the same extent as PDT, demonstrating the specificity of PDT in sensitizing immune cells to untreated tumor cells situated in deep tissue [157]. In addition to a PDT-induced systemic immune response, the impact of PDT on the microvasculature of pathologic tissues also has potential to induce therapeutic effects in deep tissue. PDT-induced endothelial damage leads to vessel contraction, vascular leakage, and basement membrane exposure [179]. In addition to serving as a potent signal for platelet aggregation via the coagulation cascade, basement membrane exposure leads to thromboxane release as well as complement cascade activation, thereby contributing to the acute inflammatory effects of PDT described above. The destructive effects of PDT on the vasculature, termed microvessel shutdown, have been exploited in therapeutic applications as a way to induce hypoxia in tumor or diseased tissue [180, 181]. The mechanism underlying PDT-induced microvessel shutdown may involve PDT based inhibition of nitric oxide (NO) release, a vasodilatory molecule, leading to local hypoxia. A study by Korebelik et al. suggested that PDT-induced inhibition of NO led to enhanced cure rates in endogenous NO producing tumors, indicating that the beneficial effects of PDT-induced vascular shutdown can be abrogated with vasodilation. In addition, tumors with low endogenous production of NO were more sensitive to Photofrin-PDT, and addition of NO inhibitors did not improve outcomes [182]. Local hypoxia at the target site coupled with PDT-induced oxidative stress to microvasculature via superoxide anion formation creates an area of tissue ischemia, which serves as a potent stimulator ofcomplement activation and neutrophil infiltration, further enhancing the PDT-induced innate immune response in addition to creating areas of hypoxia at depth [176, 182]. The mechanistic be.
