Acquired erythropoietin responsiveness of interleukin-2-dependent T lymphocytes retrovirally transduced with genes encoding chimeric erythropoietin/interleukin-2 receptors.
Adoptive immunotherapy with tumor-infiltrating lymphocytes (TILs) causes regression of some human tumors. However, the sustained proliferation and antitumor activity of TILs requires the coadministration of potentially toxic amounts of interleukin-2 (IL-2). In an effort to overcome the requirement by T cells for IL-2, we have introduced alternative growth factor receptors that use the relatively nontoxic cytokine erythropoietin (Epo) as a ligand. In our model system, the coexpression of chimeric receptors consisting of the extracellular portion of the Epo receptor (EpoR) and the intracellular portions of the IL-2 receptor subunits, beta and gamma, conferred Epo responsiveness on a T-cell line. By contrast, cells expressing the wild-type EpoR did not proliferate in response to Epo. This suggested that Epo binding caused the activation of an IL-2 signal pathway mediated by the chimeric receptors. This approach can be used to minimize toxicity and potentially improve cancer immunotherapy with TILs.
Minamoto
S
S
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Treisman
J
J
Hankins
W D
WD
Sugamura
K
K
Rosenberg
S A
SA
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004921:Erythropoietin / Q000494:pharmacology*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000494:pharmacology* / Q000633:toxicity; D016246:Lymphocytes, Tumor-Infiltrating; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000628:therapy; D017467:Receptors, Erythropoietin / Q000235:genetics* / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014162:Transfection
D007376:Interleukin-2; D017467:Receptors, Erythropoietin; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D004921:Erythropoietin