Tumor-primed, in vitro-activated CD4+ effector T cells establish long-term memory without exogenous cytokine support or ongoing antigen exposure.
Tumor-reactive T cells can be primed in vivo, then activated in vitro to provide numerical expansion and uniform acquisiton of effector phenotype and function. Adoptive transfer of effector T cells mediates complete regression of established tumors in animal models. Some experimental models indicate that extensive in vitro proliferation of T cells inhibits efficacy and that central memory T cells (T(CM)) provide greater activity than effector memory T cells (T(EM)). Clinical studies also demonstrate that persistence of adoptively transferred T cells is associated with therapeutic response, thus identifying that conditions to maximize effector cell numbers yet retain memory function are important. In this article, we demonstrate that adoptive transfer of in vitro activated effector CD4(+) T cells into tumor-free congenic mice mediates rejection of tumor challenge 9 mo later, at which time T cells re-express activation markers and undergo rapid proliferation at tumor sites. Analysis of the phenotype of memory cells in lymphoid tissues following adoptive transfer shows high CD44 expression with heterogeneous expression of CD62L, indicating a mixture of T(EM) and T(CM) phenotypes. Memory cells were sorted into two subsets based on CD62L expression levels and then activated in vitro. Although T(EM) cells proliferated more rapidly, T(EM) and T(CM) cells acquired effector phenotype and function. These data indicate that controlled in vitro expansion of tumor-reactive T cells for adoptive immunotherapy also provides a competent memory response.
Wang
Li-Xin
LX
Department of Immunology, Cleveland Clinic, Cleveland, OH 44195, USA.
Plautz
Gregory E
GE
D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage* / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000008:administration & dosage / Q000502:physiology; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology / Q000473:pathology / Q000556:secondary / Q000628:therapy; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive / Q000379:methods; D019041:L-Selectin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary / Q000628:therapy; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation / Q000276:immunology / Q000473:pathology
D000951:Antigens, Neoplasm; D016207:Cytokines; D019041:L-Selectin
Nature. 2007 Dec 6;450(7171):903-7
18026089
J Clin Oncol. 2005 Apr 1;23(10):2346-57
15800326
J Immunother. 2005 May-Jun;28(3):258-67
15838383
J Immunol. 2004 Dec 15;173(12):7125-30
15585832
J Immunol. 2002 Nov 1;169(9):4811-21
12391191
Immunity. 2005 Mar;22(3):371-83
15780993
Nat Rev Immunol. 2006 May;6(5):383-93
16622476
Blood. 2007 Oct 15;110(8):2838-45
17609424
Annu Rev Immunol. 2007;25:171-92
17129182
Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16689-94
18946035
Curr Opin Immunol. 2004 Jun;16(3):259-63
15134772
Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9571-6
15980149
Science. 2009 Jan 23;323(5913):505-9
19164749
Science. 1999 Nov 12;286(5443):1381-3
10558997
Immunity. 2008 Apr;28(4):533-45
18356084
Nat Med. 2001 Aug;7(8):913-9
11479623
Nature. 2009 Jul 2;460(7251):108-12
19543266
J Transl Med. 2004 Nov 26;2(1):41
15566571
Nat Immunol. 2004 Sep;5(9):927-33
15300249
J Immunol. 2004 Dec 1;173(11):6694-702
15557161
Immunity. 2008 Dec 19;29(6):848-62
19100699
Annu Rev Immunol. 2007;25:243-65
17129181
Science. 1995 Apr 7;268(5207):106-11
7535476
J Immunol. 2002 Feb 15;168(4):1528-32
11823476
J Immunol. 2000 Oct 1;165(7):3656-62
11034369
Nat Rev Cancer. 2008 Apr;8(4):299-308
18354418
J Immunol. 2004 Mar 15;172(6):3462-8
15004146
Blood. 2007 Jun 15;109(12):5346-54
17327412
Immunity. 2004 Aug;21(2):137-48
15308095
Immunity. 2007 Oct;27(4):670-84
17950003
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16168-73
12427970
J Clin Invest. 2008 Jan;118(1):294-305
18060041
J Immunol. 1990 Feb 15;144(4):1531-7
2303716
Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):652-6
18178624
Blood. 2007 Jun 1;109(11):4865-76
17284532
PLoS One. 2009;4(3):e4749
19270751
J Exp Med. 2005 May 16;201(10):1555-65
15897273
Cancer Res. 1996 Oct 1;56(19):4338-42
8813119
J Clin Oncol. 2008 Nov 10;26(32):5233-9
18809613