Radiotherapy and immunotherapy converge on elimination of tumor-promoting erythroid progenitor cells through adaptive immunity

Yuzhu Hou, Hua L. Liang, Xinshuang Yu, Zhida Liu, Xuezhi Cao, Enyu Rao, Xiaona Huang, Liangliang Wang, Lei Li, Jason Bugno, Yanbin Fu, Steven J. Chmura, Wenjun Wu, Sean Z. Luo, Wenxin Zheng, Ainhoa Arina, Jessica Jutzy, Anne R. McCall, Everett E. Vokes, Sean P. PitrodaYang Xin Fu, Ralph R. Weichselbaum

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Tumor-induced CD45Ter119+CD71+ erythroid progenitor cells, termed “Ter cells,” promote tumor progression by secreting artemin (ARTN), a neurotrophic peptide that activates REarranged during Transfection (RET) signaling. We demonstrate that both local tumor ionizing radiation (IR) and anti-programmed death ligand 1 (PD-L1) treatment decreased tumor-induced Ter cell abundance in the mouse spleen and ARTN secretion outside the irradiation field in an interferon- and CD8+ T cell-dependent manner. Recombinant erythropoietin promoted resistance to radiotherapy or anti-PD-L1 therapies by restoring Ter cell numbers and serum ARTN concentration. Blockade of ARTN or potential ARTN signaling partners, or depletion of Ter cells augmented the antitumor effects of both IR and anti-PD-L1 therapies in mice. Analysis of samples from patients who received radioimmunotherapy demonstrated that IR-mediated reduction of Ter cells, ARTN, and GFRα3, an ARTN signaling partner, were each associated with tumor regression. Patients with melanoma who received immunotherapy exhibited favorable outcomes associated with decreased expression of GFRα3. These findings demonstrate an out-of-field, or “abscopal,” effect mediated by adaptive immunity, which is induced during local tumor irradiation. This effect, in turn, governs the therapeutic effects of radiation and immunotherapy. Therefore, our results identify multiple targets to potentially improve outcomes after radiotherapy and immunotherapy.

Original languageEnglish (US)
Article numbereabb0130
JournalScience translational medicine
Issue number582
StatePublished - Feb 24 2021

ASJC Scopus subject areas

  • Medicine(all)


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