TY - JOUR
T1 - Radiotherapy and immunotherapy converge on elimination of tumor-promoting erythroid progenitor cells through adaptive immunity
AU - Hou, Yuzhu
AU - Liang, Hua L.
AU - Yu, Xinshuang
AU - Liu, Zhida
AU - Cao, Xuezhi
AU - Rao, Enyu
AU - Huang, Xiaona
AU - Wang, Liangliang
AU - Li, Lei
AU - Bugno, Jason
AU - Fu, Yanbin
AU - Chmura, Steven J.
AU - Wu, Wenjun
AU - Luo, Sean Z.
AU - Zheng, Wenxin
AU - Arina, Ainhoa
AU - Jutzy, Jessica
AU - McCall, Anne R.
AU - Vokes, Everett E.
AU - Pitroda, Sean P.
AU - Fu, Yang Xin
AU - Weichselbaum, Ralph R.
N1 - Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
PY - 2021/2/24
Y1 - 2021/2/24
N2 - Tumor-induced CD45−Ter119+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.
AB - Tumor-induced CD45−Ter119+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.
UR - http://www.scopus.com/inward/record.url?scp=85101780073&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85101780073&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.abb0130
DO - 10.1126/scitranslmed.abb0130
M3 - Article
C2 - 33627484
AN - SCOPUS:85101780073
SN - 1946-6234
VL - 13
JO - Science translational medicine
JF - Science translational medicine
IS - 582
M1 - eabb0130
ER -