Response to radiotherapy in pancreatic ductal adenocarcinoma is enhanced by inhibition of myeloid-derived suppressor cells using STAT3 anti-sense oligonucleotide

Advances in Targeting Cancer-Associated Genes by Designed siRNA in Prostate Cancer

“…Therefore, alleviation of MDSC-mediated immunosuppression is an effective method to restore immune activity against cancer. It has been confirmed that STAT3 is activated in circulating MDSCs and has a decisive role in MDSC-mediated immunosuppression [73]. It was shown that immunosuppressive impacts of patient-derived MDSCs on effector CD8 (+) T cells can be abrogated through delivery of STAT3-siRNA to MDSCs [74].…”

How Macrophages Become Transcriptionally Dysregulated: A Hidden Impact of Antitumor Therapy

“…The generalized effect of X-ray and 𝛾-photon radiotherapy is STAT3 activation, which is observed in TAMs in response to all clinical doses of radiation. Irradiation promotes IL-6 production by the tumor microenvironment, which results in STAT3 phosphorylation and subsequent anti-inflammatory CCL2, CCL4, VEGF, and TGF-β cytokine production [ 149 , 158 , 160 , 189 ]. It is worth noting that STAT3 signaling also promotes cell survival after irradiation exposure via induction of anti-apoptotic proteins (survivin and Bcl-2), and this effect is more profound for M2-like TAMs [ 158 , 160 , 190 ].…”

“…Irradiation promotes IL-6 production by the tumor microenvironment, which results in STAT3 phosphorylation and subsequent anti-inflammatory CCL2, CCL4, VEGF, and TGF-β cytokine production [ 149 , 158 , 160 , 189 ]. It is worth noting that STAT3 signaling also promotes cell survival after irradiation exposure via induction of anti-apoptotic proteins (survivin and Bcl-2), and this effect is more profound for M2-like TAMs [ 158 , 160 , 190 ]. The low radiation doses show a bidirectional impact on the anti-inflammatory TFs, comprised of STAT3 stimulation, as mentioned earlier, and STAT6 suppression with high IL-5 and 13 and low TGF-β cytokine profile [ 150 , 156 ].…”

“…STAT family-based immunotherapy can enhance the effects of ɣ-radiation via regulation of macrophage subset and cytokine balance in the tumor microenvironment [ 281 ]. For instance, tyrosine kinase inhibitors (sunitinib, sorafenib), WP1066, plant-derived imodin (PM37), and resveratrol inhibit STAT TF activity in macrophages and restricts M2 polarization, suggesting the improved antitumor reactivity against pancreatic adenocarcinoma, breast, and lung cancer [ 49 , 160 , 191 , 258 , 282 , 283 , 284 ]. Additionally, STATs, IRFs, NF-κB, and c-MYC mediated polarization can be regulated by microRNAs.…”

“…1.5 Gy X-ray induces macrophage polarization toward M1 phenotype via STAT6 suppression while 5–10 Gy proton irradiation induces M1 phenotype via p50-p65 nuclear translocation [ 68 , 156 ]. Two or eight Gy X-ray induce M2 phenotype via STAT3 activation while 0.5–0.7 Gy X-ray down-regulates M1 markers via inhibition of p65 nuclear transport [ 158 , 160 , 173 ].…”