Research ArticleCancer

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

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Science Translational Medicine  24 Feb 2021:
Vol. 13, Issue 582, eabb0130
DOI: 10.1126/scitranslmed.abb0130

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“Ter”-ning a corner on cancer therapy

Tumor cells exploit numerous signaling pathways to promote malignant progression. One such pathway is mediated by the neurotrophic peptide ARTN. ARTN is secreted by a population of erythroid progenitor cells called Ter cells and is thought to mediate both metastasis and survival. In this study, Hou et al. found that both radiotherapy and immunotherapy are able to deplete Ter cells, subsequently reducing ARTN production and tumor progression. Ter cell depletion was dependent on an intact adaptive immune response and mediated by interferon γ. Combinations of Ter cell depletion, blockade of ARTN signaling, radiotherapy, and immunotherapy led to enhanced control of tumor burden in mice. Thus, targeting Ter cells through combination therapy is an attractive option for cancer treatment.

Abstract

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.

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