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Hou Y , Liang HL , Yu X , Liu Z , Cao X , Rao E , Huang X , Wang L , Li L , Bugno J , Fu Y , Chmura SJ , Wu W , Luo SZ , Zheng W , Arina A , Jutzy J , McCall AR , Vokes EE , Pitroda SP , Fu YX , Weichselbaum RR
Radiotherapy and immunotherapy converge on elimination of tumor-promoting erythroid progenitor cells through adaptive immunity
Sci Transl Med. 2021 Feb 24;13(582)
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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.
1946-6242 Hou, Yuzhu Orcid: 0000-0001-8274-027x Liang, Hua L Orcid: 0000-0001-5512-8595 Yu, Xinshuang Orcid: 0000-0001-9095-3435 Liu, Zhida Orcid: 0000-0002-3980-8440 Cao, Xuezhi Orcid: 0000-0002-3602-4560 Rao, Enyu Huang, Xiaona Wang, Liangliang Orcid: 0000-0001-8340-5190 Li, Lei Bugno, Jason Orcid: 0000-0002-3046-8072 Fu, Yanbin Chmura, Steven J Orcid: 0000-0001-8851-7108 Wu, Wenjun Luo, Sean Z Zheng, Wenxin Arina, Ainhoa Orcid: 0000-0002-0585-7148 Jutzy, Jessica Orcid: 0000-0001-9699-7957 McCall, Anne R Orcid: 0000-0001-6029-3915 Vokes, Everett E Orcid: 0000-0002-8645-8068 Pitroda, Sean P Fu, Yang-Xin Orcid: 0000-0002-4809-825x Weichselbaum, Ralph R Orcid: 0000-0002-5643-8939 Journal Article United States Sci Transl Med. 2021 Feb 24;13(582):eabb0130. doi: 10.1126/scitranslmed.abb0130.