title: Chimeric γc cytokine receptors confer cytokine independent engraftment of human T lymphocytes.
abstract: Therapeutic responses following adoptive transfer of T cells correlate to levels of long-term T cell persistence. Lymphodepletion and exogenous γc cytokine administration can improve T cell persistence following adoptive transfer, but their effects are not uniform and toxicities are significant. To overcome these limitations, we designed a chimeric γc cytokine receptor (CγCR) composed of Interleukin-7 (IL-7) tethered to IL-7Rα/CD127 that confers exogenous cytokine independent, cell intrinsic, STAT5 cytokine signals. We additionally show that this design is modular in that the IL-2Rβ/CD122 cytoplasmic chain can be exchanged for that of IL-7Rα/CD127, enhancing Shc activity. When expressed in central memory-derived primary human CD8(+) CTL (T(E/CM)), these CγCRs signal according to their corresponding wild-type counterparts to support exogenous cytokine independent viability and homeostatic proliferation, while retaining full effector function. In vivo studies demonstrate that both CγCR-CD127(+) and CγCR-CD122(+) CD8(+) T((E/CM)) engraft in mice and persist in an absence of exogenous cytokine administration. Engrafted CγCR-CD127(+) CD8(+) T(E/CM) preferentially retain central memory marker expression in vivo demonstrating a dichotomy between CD127 versus CD122 signaling. Together, these results suggest that expression of CγCR in therapeutic T cells may aid in the in vivo persistence of these cells, particularly under conditions of limiting homeostatic cytokines.
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Hunter
authors.forename: Megan E
authors.initials: ME
authors.lastname: Prosser
authors.forename: Vaidehi
authors.initials: V
authors.lastname: Mahadev
authors.forename: Xiuli
authors.initials: X
authors.lastname: Wang
authors.forename: Brenda
authors.initials: B
authors.lastname: Aguilar
authors.forename: Christine E
authors.initials: CE
authors.lastname: Brown
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jensen
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology / Q000494:pharmacology; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015851:Interleukin-7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D014183:Transplantation, Heterologous
chemical_list: D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D053646:Interleukin-2 Receptor beta Subunit; D015851:Interleukin-7; D020395:Receptors, Interleukin-7; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D055765:Shc Signaling Adaptor Proteins; C415350:interleukin-7 receptor, alpha chain