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Induction of an acute vitamin A-deficient state following total body irradiation impairs anti-tumor immunity by altering the homeostasis of pre-cDC derived dendritic cells

Host conditioning with total body irradiation (TBI) can potently augment adoptive T cell (ACT) immunotherapies by removal of sinks for homeostatic cytokines such as IL-7 and IL-15, depletion of CD4+ Tregs, and liberation of endogenous toll like-receptor agonists. Clinically, TBI-conditioning prior to ACT has been associated with durable complete responses in nearly 40% of patients with metastatic melanoma. However, TBI-conditioning also leads to dose-dependent mucosal injury and significant weight loss in the majority of treated patients. To explore the potential immunologic impact of this acute metabolic and nutritional perturbation, we profiled circulating micro-nutrients in the serum of TBI-conditioned patients and tumor-bearing mice receiving ACT. Unexpectedly, we found that TBI induced an acute vitamin A deficient (VAD) state. Immunologically, this state was associated with a selective loss in the splenic CD11b+CD8α-Esamhigh (CD11b+) DC subset, the predominant DC subset in the spleen under steady state conditions which is specialized for class II antigen processing and presentation. By contrast, the CD11b-CD8α+ (CD8α+) DC subset, which is specialized for Ag cross-presentation to CD8+ T cells, was unaffected. Provision of exogenous retinoic acid (RA), the activated metabolite of vitamin A, restored the CD11b+ DC population following TBI. Further, evaluation of mice maintained on a VAD diet also demonstrated a CD11b+ DC defect that could be rescued by RA add-back, confirming that vitamin A is required in the physiologic maintenance of the CD11b+ subset. Mechanistically, VAD did not impair the formation of pre-DCs, the immediate hematopoetic progenitor of both the CD11b+ and CD8α+ DC subsets. Rather, in fate-tracking experiments, transfer of pre-DC into RA-supplemented hosts resulted in near complete conversion into the CD11b+ subset whereas transfer into VAD hosts caused diversion to the CD8α+lineage. Functionally, TBI-induced vitamin A deficiency resulted in impaired antitumor immunity mediated by ACT of CD4+ but not CD8+ T cells which could be rescued by supplemental RA. These findings establish a critical role for vitamin A in regulating the homeostasis of pre-DC derived DC subsets. Moreover, these data demonstrate how the nutritional and metabolic status of the tumor-hearing host can have a profound influence on therapeutic outcomes to vaccine and adoptive T cell immunotherapies.

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Correspondence to Christopher A Klebanoff.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Keywords

  • Retinoic Acid
  • Total Body Irradiation
  • Antitumor Immunity
  • Durable Complete Response
  • Exogenous Retinoic Acid