title: Effector CD8+ T-cell Engraftment and Antitumor Immunity in Lymphodepleted Hosts Is IL7Rα Dependent.
abstract: Adoptive cellular therapy, in which activated tumor-reactive T cells are transferred into lymphodepleted recipients, is a promising cancer treatment option. Activation of T cells decreases IL7 responsiveness; therefore, IL15 is generally considered the main driver of effector T-cell responses in this setting. However, we found in lymphodepleted mice that CD8(+) T cells activated with IL12 showed enhanced engraftment that was initially dependent on host IL7, but not IL15. Mechanistically, enhanced IL7 responsiveness was conferred by elevated IL7Rα expression, which was critical for antitumor immunity. Elevated IL7Rα expression was achievable without IL12, as polyclonal CD8(+) T cells activated with high T-cell receptor (TCR) stimulation depended on T-cell IL7Rα expression and host IL7 for maximal engraftment. Finally, IL12 conditioning during the activation of human CD8(+) T cells, including TCR-modified T cells generated using a clinically relevant protocol, led to enhanced IL7Rα expression. Our results demonstrate the importance of the donor IL7Rα/host IL7 axis for effector CD8(+) T-cell engraftment and suggest novel strategies to improve adoptive cellular therapy as a cancer treatment.
authors: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors: C Bryce
authors: CB
authors: Johnson
authors: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors: Brian P
authors: BP
authors: Riesenberg
authors: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors: Bennett R
authors: BR
authors: May
authors: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors: Stuart C
authors: SC
authors: Gilreath
authors: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors: Guangfu
authors: G
authors: Li
authors: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors: Kevin F
authors: KF
authors: Staveley-O'Carroll
authors: Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina.
authors: Elizabeth
authors: E
authors: Garrett-Mayer
authors: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors: Shikhar
authors: S
authors: Mehrotra
authors: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors: David J
authors: DJ
authors: Cole
authors: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina. markrubinstein@musc.edu.
authors: Mark P
authors: MP
authors: Rubinstein
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D045744:Cell Line, Tumor; D006801:Humans; D053765:Interleukin-12 Subunit p35 / Q000096:biosynthesis / Q000276:immunology*; D019409:Interleukin-15 / Q000096:biosynthesis / Q000276:immunology; D015851:Interleukin-7 / Q000096:biosynthesis / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis* / Q000276:immunology
chemical_list: C508859:Il12a protein, mouse; D053765:Interleukin-12 Subunit p35; D019409:Interleukin-15; D015851:Interleukin-7; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain