Article Text

Download PDFPDF

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
  1. Christopher A Klebanoff1,
  2. Sean Spencer2,
  3. Rahu Roychoudhuri1,
  4. Yun Ji1,
  5. Madhu Sukumar1,
  6. Pawel Muranski1,
  7. Joseph L Napoli3,
  8. Luca Gattinoni1,
  9. Yasmine Belkaid2 and
  10. Nicholas P Restifo1
  1. Aff1 CCR/NCI Bethesda MD USA
  2. Aff2 grid.419681.30000000121649667NIAID/NIH Bethesda MD USA
  3. Aff3 grid.148313.c0000000404283079Program in Metabolic Biology, Nutritional Science and ToxicologyUniversity of California Berkley CA USA

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Meeting abstracts

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.