Myeloid cell–targeted STAT3 inhibition sensitizes head and neck cancers to radiotherapy and T cell–mediated immunity

Abstract

Conflict of interest statement: M.K. and D.M. are inventors on the patent application submitted by COH that covers the design of oligonucleotides presented in this report. M.K. is a co-founder of iSTAT Therapeutics Inc. and a scientific advisor to Scopus Biopharma Inc., companies focused on oligonucleotidebased cancer immunotherapies. All other authors declare no potential conflict of interest. Total word count (whole manuscript): 7872 Total number of figures and tables: 6 References: 50 Summary: The combination of STAT3 targeting and TLR9 stimulation within head and neck cancerassociated myeloid cells enhances T cell-mediated antitumor immune responses after local radiation therapy.

Novel Target Opportunities in Non-Metastatic Castrate Resistant Prostate Cancer

“…These preclinical results underscore therapeutic potential and priority in targeting STAT3 activity in tumor-associated immune cells rather than in cancer cells alone [53,62]. Synergistic activity of anti-STAT3 inhibitors on tumor microenvironment might be just as important as its anti-tumor activity in prostate cancer [63].…”

At the Crossroads of Molecular Biology and Immunology: Molecular Pathways for Immunological Targeting of Head and Neck Squamous Cell Carcinoma

“…In a recent in vitro study in breast cancer sentinel lymph nodes (SLN), van Pul et al showed that STAT3 inhibition in immune cells, combined with immune stimulation through TLR9 using CpG-B, could activate dendritic cell (DC) subsets in SLN cultures and increased tumor-specific T cell responses [52]. Using in vivo HNSCC mouse models, Moreira et al showed that a STAT3-inhibiting oligonucleotide linked to CpG specifically targeted to myeloid cells, increased tumor sensitivity to radiotherapy and increased the anti-tumor immune response, suggesting that this could be a valid pathway to target in HNSCC [53]. In a syngeneic carcinogen-induced immune competent HNSCC mouse model, a small molecule inhibitor HNC0014, targeting cMET/STAT3/CD44 and PD-L1, was shown to reduce tumor growth, pSTAT3 and PD-L1 levels in tumors and increase T cell frequencies in the circulation most efficiently when combined with anti-PD-L1 treatment [48].…”

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 ].…”

“…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 ].…”