Adoptive transfer of gene-engineered CD4+ helper T cells induces potent primary and secondary tumor rejection.
Because CD4+ T cells play a key role in aiding cellular immune responses, we wanted to assess whether increasing numbers of gene-engineered antigen-restricted CD4+ T cells could enhance an antitumor response mediated by similarly gene-engineered CD8+ T cells. In this study, we have used retroviral transduction to generate erbB2-reactive mouse T-cell populations composed of various proportions of CD4+ and CD8+ cells and then determined the antitumor reactivity of these mixtures. Gene-modified CD4+ and CD8+ T cells were shown to specifically secrete Tc1 (T cytotoxic-1) or Tc2 cytokines, proliferate, and lyse erbB2+ tumor targets following antigen ligation in vitro. In adoptive transfer experiments using severe combined immunodeficient (scid) mice, we demonstrated that injection of equivalent numbers of antigen-specific engineered CD8+ and CD4+ T cells led to significant improvement in survival of mice bearing established lung metastases compared with transfer of unfractionated (largely CD8+) engineered T cells. Transferred CD4+ T cells had to be antigen-specific (not just activated) and secrete interferon gamma (IFN-gamma) to potentiate the antitumor effect. Importantly, antitumor responses in these mice correlated with localization and persistence of gene-engineered T cells at the tumor site. Strikingly, mice that survived primary tumor challenge could reject a subsequent rechallenge. Overall, this study has highlighted the therapeutic potential of using combined transfer of antigen-specific gene-modified CD8+ and CD4+ T cells to significantly enhance T-cell adoptive transfer strategies for cancer therapy.
Moeller
Maria
M
Cancer Immunology Program, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, East Melbourne, 8006, Victoria, Australia.
Haynes
Nicole M
NM
Kershaw
Michael H
MH
Jackson
Jacob T
JT
Teng
Michele W L
MW
Street
Shayna E
SE
Cerutti
Loretta
L
Jane
Stephen M
SM
Trapani
Joseph A
JA
Smyth
Mark J
MJ
Darcy
Phillip K
PK
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D005818:Genetic Engineering; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D057127:Single-Chain Antibodies; D015996:Survival Rate; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism*
D016207:Cytokines; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; C496415:scFv-CD28-zeta chimeric receptor; D007371:Interferon-gamma