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

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.

A CTL/M2 macrophage-related four-gene signature predicting metastasis-free survival in triple-negative breast cancer treated with adjuvant radiotherapy

“…Many previous studies have shown that the immune system plays an important role in mediating the antitumor effects of RT [35,36]. For instance, RT can activate the antitumor immune effect by inducing the maturation of dendritic cells and enhancing the activation of T cells [37,38].…”

Potent but transient immunosuppression of T-cells is a general feature of CD71+ erythroid cells

“…Recent studies demonstrated that immunomodulatory properties are strong in early-stage CD45 + CECs in contrast to more mature CD45 − CECs that lack these capacities 9 , 10 , 17 , 44 . However, other studies also reported the immunomodulatory role of CD45 − CECs 41 , 45 , which suggests that CD45 alone may not be a reliable marker of immunosuppressive CECs. Here, we showed that human CECs acquire immunomodulatory properties during erythroid differentiation and are the most potent in an early stage characterized by the CD71 high CD235a mid phenotype.…”

Potent but transient immunosuppression of T-cells is a general feature of CD71+erythroid cells

“…Recent studies demonstrated that immunomodulatory properties are strong in early-stage CD45 + CECs in contrast to more mature CD45 -CECs that lack these capacities 9,10,17,43 . However, other studies also reported the immunomodulatory role of CD45 -CECs 40,44 , which suggests that CD45 alone may not be a reliable marker of immunosuppressive CECs. Here, we showed that human CECs acquire immunomodulatory properties during erythroid differentiation and are the most potent in an early stage characterized by the CD71 high CD235a mid phenotype.…”