Adoptive cell therapy for lymphoma with CD4 T cells depleted of CD137-expressing regulatory T cells.
Adoptive immunotherapy with antitumor T cells is a promising novel approach for the treatment of cancer. However, T-cell therapy may be limited by the cotransfer of regulatory T cells (T(reg)). Here, we explored this hypothesis by using 2 cell surface markers, CD44 and CD137, to isolate antitumor CD4 T cells while excluding T(regs). In a murine model of B-cell lymphoma, only CD137(neg)CD44(hi) CD4 T cells infiltrated tumor sites and provided protection. Conversely, the population of CD137(pos)CD44hi CD4 T cells consisted primarily of activated T(regs). Notably, this CD137(pos) T(reg) population persisted following adoptive transfer and maintained expression of FoxP3 as well as CD137. Moreover, in vitro these CD137(pos) cells suppressed the proliferation of effector cells in a contact-dependent manner, and in vivo adding the CD137(pos)CD44(hi) CD4 cells to CD137(neg)CD44(hi) CD4 cells suppressed the antitumor immune response. Thus, CD137 expression on CD4 T cells defined a population of activated T(regs) that greatly limited antitumor immune responses. Consistent with observations in the murine model, human lymphoma biopsies also contained a population of CD137(pos) CD4 T cells that were predominantly CD25(pos)FoxP3(pos) T(regs). In conclusion, our findings identify 2 surface markers that can be used to facilitate the enrichment of antitumor CD4 T cells while depleting an inhibitory T(reg) population.
Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
Matthew J
MJ
Goldstein
Holbrook E
HE
Kohrt
Roch
R
Houot
Bindu
B
Varghese
Jack T
JT
Lin
Erica
E
Swanson
Ronald
R
Levy
D019264:Adoptive Transfer; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D051858:Forkhead Transcription Factors; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis*; D007108:Immune Tolerance; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000032:analysis*
D015415:Biomarkers; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018960:Hyaluronan Receptors; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9