title: Dendritic Cells in Irradiated Mice Trigger the Functional Plasticity and Antitumor Activity of Adoptively Transferred Tc17 Cells via IL12 Signaling.
abstract: OBJECTIVE
  The adoptive cell transfer (ACT) of CD8(+) T cells is a promising treatment for advanced malignancies. Lymphodepletion before ACT enhances IFNγ(+)CD8(+) T cell (Tc0)-mediated tumor regression. Yet, how lymphodepletion regulates the function and antitumor activity of IL17A(+)CD8(+) T cells (Tc17) is unknown.
  
  
  METHODS
  To address this question, pmel-1 CD8(+) T cells were polarized to secrete either IL17A or IFNγ. These subsets were then infused into mice with B16F10 melanoma that were lymphoreplete [no total body irradiation (TBI)], or lymphodepleted with nonmyeloablative (5 Gy) or myeloablative (9 Gy with hematopoietic stem cell transplantation) TBI. The activation of innate immune cells and function of donor T-cell subsets were monitored in recipient mice.
  
  
  RESULTS
  Tc17 cells regress melanoma in myeloablated mice to a greater extent than in lymphoreplete or nonmyeloablated mice. TBI induced functional plasticity in Tc17 cells, causing conversion from IL17A to IFNγ producers. Additional investigation revealed that Tc17 plasticity and antitumor activity were mediated by IL12 secreted by irradiated host dendritic cells (DC). Neutralization of endogenous IL12 reduced the antitumor activity of Tc17 cells in myeloablated mice, whereas ex vivo priming with IL12 enhanced their capacity to regress melanoma in nonmyeloablated animals. This, coupled with exogenous administration of low-dose IL12, obviated the need for host preconditioning, creating curative responses in nonirradiated mice.
  
  
  CONCLUSIONS
  Our findings indicate that TBI-induced IL12 augments Tc17 cell-mediated tumor immunity and underline the substantial implications of in vitro preparation of antitumor Tc17 cells with IL12 in the design of T-cell immunotherapies.
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. bowersjs@musc.edu paulos@musc.edu.
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Bowers
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Michelle H
authors.initials: MH
authors.lastname: Nelson
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Sreenath
authors.initials: S
authors.lastname: Kundimi
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Stefanie R
authors.initials: SR
authors.lastname: Bailey
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Logan W
authors.initials: LW
authors.lastname: Huff
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Schwartz
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cole
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Rubinstein
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. bowersjs@musc.edu paulos@musc.edu.
authors.forename: Chrystal M
authors.initials: CM
authors.lastname: Paulos
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000637:transplantation; D003713:Dendritic Cells / Q000276:immunology / Q000528:radiation effects; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D015398:Signal Transduction / Q000528:radiation effects; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014916:Whole-Body Irradiation
chemical_list: D020381:Interleukin-17; D018664:Interleukin-12