Combined modality radiation therapy promotes tolerogenic myeloid cell populations and STAT3-related gene expression in head and neck cancer patients
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Sagus Sampath1,*, Haejung Won2,*, Erminia Massarelli3, Min Li4, Paul Frankel4, Nayana Vora1, Lalit Vora1, Ellie Maghami5 and Marcin Kortylewski2
1Radiation Oncology Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
2Immuno-Oncology Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
3Medical Oncology Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
4Department of Biostatistics, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
5Surgery Department Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
*These authors have contributed equally to this work
Marcin Kortylewski, email: [email protected]
Keywords: head and neck squamous cell carcinoma; radiation therapy; immunosuppression; IL-6; STAT3
Received: September 19, 2017 Accepted: January 24, 2018 Published: February 02, 2018
Immunomodulation contributes to the antitumor efficacy of the fractionated radiation therapy (RT). Here, we describe immune effects of RT with concurrent systemic cisplatin or cetuximab treatment of patients with stage III-IV head and neck squamous cell carcinoma (HNSCC). Using longitudinally collected blood samples, we identified significant changes in cytokines/chemokines and immune cell populations compared to immune-related gene expression profiles in peripheral blood mononuclear cells (PBMCs). The 7-week combinatorial RT resulted in gradual elevation of proinflammatory mediators (IFNγ, IL-6, TNFα, CCL2), while levels of IL-12, cytokine essential for antitumor immune responses, were decreased. These effects correlated with progressive accumulation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) with detectable activity of STAT3 and PD-L1 expression, underscoring tolerogenic effects of MDSCs. Correspondingly, gene expression analysis of PBMCs harvested after two weeks of combinatorial RT, found upregulation of several immunosuppressive mediators. These included IL6, IL6R, STAT3 and PDL1, which could represent IL-6/STAT3-driven tolerogenic signaling, which inhibits T cell and NK activity. Overall, our results suggest that potential immunostimulatory effects of combinatorial RT in HNSCC patients are likely limited by tolerogenic STAT3 signaling and PD-L1 upregulation in myeloid immune cells. Further studies will clarify whether STAT3 targeting could augment RT efficacy and durability of antitumor responses.
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