Radiotherapy and immunotherapy converge on elimination of tumor-promoting erythroid progenitor cells through adaptive immunity. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • February 24, 2021

Research

keywords

  • Erythroid Precursor Cells
  • Neoplasms

Identity

PubMed Central ID

  • PMC8710940

Scopus Document Identifier

  • 85101780073

Digital Object Identifier (DOI)

  • 10.1038/nmeth.2089

PubMed ID

  • 33627484

Additional Document Info

volume

  • 13

issue

  • 582