Adoptive T-cell transfer (ACT) is successfully applied as a cancer treatment that is based on the activation and effector functions of tumor-specific T cells. Here, we present results from a mouse... Show moreAdoptive T-cell transfer (ACT) is successfully applied as a cancer treatment that is based on the activation and effector functions of tumor-specific T cells. Here, we present results from a mouse model in which ACT is combined with a long peptide-based vaccine comprising gp100 T-cell epitopes. Transferred CD8(+) T cells expanded up to 1,000-fold after peptide vaccination, leading to a 3-fold increase in white blood cell count and a very high frequency in the generation of antigen-specific memory T cells, the generation of which tended to correlate with effective antitumor responses. An enormous pool of effector T cells spread widely to different tissues, including the skin and the immune-privileged eye, where they mediate tumor eradication. Importantly, these striking T-cell dynamics occurred in immunocompetent mice without prior hematologic conditioning. Continued activation of the specific T-cell pool by vaccination led to strong T-cell-mediated cytokine storm and lethality due to multi-organ failure. However, this immunopathology could be prevented by controlling the rapid biodistribution of the peptide or by using a weakly agonistic peptide. Together, these results identify a peptide vaccination strategy that can potently accentuate effective ACT in non-lymphodepleted hosts. Cancer Res; 70(21); 8339-46. (C) 2010 AACR. Show less
Fransen, M.F.; Stipdonk, M.J. van; Sluijter, M.; Schoenberger, S.P.; Melief, C.J.; Offringa, R. 2010
Priming of naive CD8(+) T cells by pathogens or vaccines generally involves their interaction with Ag-loaded dendritic cells (DCs) in the context of an inflamed lymph node. Lymph node activation... Show morePriming of naive CD8(+) T cells by pathogens or vaccines generally involves their interaction with Ag-loaded dendritic cells (DCs) in the context of an inflamed lymph node. Lymph node activation fosters DC and T cell encounters and subsequently provides newly primed T cells with nurturing conditions. We dissected these two aspects by infusing in vitro primed CD8(+) T cells into naive recipient mice harboring a single activated lymph node and comparing the fate of these T cells with those infused into control recipients. Brief (20 h) in vitro priming empowered the T cells to expand in vivo without further Ag stimulation. This primary response was not affected by the presence or absence of a nonspecifically activated lymph node. In contrast, in vivo antigenic challenge after contraction of the primary response resulted in significantly stronger secondary T cell responses in mice harboring activated lymph nodes, demonstrating that the availability of an activated lymph node supported the generation of T cell memory in an Ag-unrelated manner. The presence of an activated lymph node during the expansion and contraction phase of the primary response did not endow T cells with an instructional program for increased survival or secondary expansion, but primarily served to conserve increased numbers of T cells. Show less
Fransen, M.F.; Stipdonk, M.J. van; Sluijter, M.; Schoenberger, S.P.; Melief, C.J.; Offringa, R. 2010
Priming of naive CD8(+) T cells by pathogens or vaccines generally involves their interaction with Ag-loaded dendritic cells (DCs) in the context of an inflamed lymph node. Lymph node activation... Show morePriming of naive CD8(+) T cells by pathogens or vaccines generally involves their interaction with Ag-loaded dendritic cells (DCs) in the context of an inflamed lymph node. Lymph node activation fosters DC and T cell encounters and subsequently provides newly primed T cells with nurturing conditions. We dissected these two aspects by infusing in vitro primed CD8(+) T cells into naive recipient mice harboring a single activated lymph node and comparing the fate of these T cells with those infused into control recipients. Brief (20 h) in vitro priming empowered the T cells to expand in vivo without further Ag stimulation. This primary response was not affected by the presence or absence of a nonspecifically activated lymph node. In contrast, in vivo antigenic challenge after contraction of the primary response resulted in significantly stronger secondary T cell responses in mice harboring activated lymph nodes, demonstrating that the availability of an activated lymph node supported the generation of T cell memory in an Ag-unrelated manner. The presence of an activated lymph node during the expansion and contraction phase of the primary response did not endow T cells with an instructional program for increased survival or secondary expansion, but primarily served to conserve increased numbers of T cells. The Journal of Immunology, 2010, 185: 3167-3173. Show less
Oliveira, C.C.; Veelen, P.A. van; Querido, B.; Ru, A. de; Sluijter, M.; Laban, S.; ... ; Hall, T. van 2010
The nonclassical major histocompatibility complex (MHC) Qa-1b accommodates monomorphic leader peptides and functions as a ligand for germ line receptors CD94/NKG2, which are expressed by natural... Show moreThe nonclassical major histocompatibility complex (MHC) Qa-1b accommodates monomorphic leader peptides and functions as a ligand for germ line receptors CD94/NKG2, which are expressed by natural killer cells and CD8+ T cells. We here describe that the conserved peptides are replaced by a novel peptide repertoire of surprising diversity as a result of impairments in the antigen-processing pathway. This novel peptide repertoire represents immunogenic neoantigens for CD8+ T cells, as we found that these Qa-1b-restricted T cells dominantly participated in the response to tumors with processing deficiencies. A surprisingly wide spectrum of target cells, irrespective of transformation status, MHC background, or type of processing deficiency, was recognized by this T cell subset, complying with the conserved nature of Qa-1b. Target cell recognition depended on T cell receptor and Qa-1b interaction, and immunization with identified peptide epitopes demonstrated in vivo priming of CD8+ T cells. Our data reveal that Qa-1b, and most likely its human homologue human leukocyte antigen-E, is important for the defense against processing-deficient cells by displacing the monomorphic leader peptides, which relieves the inhibition through CD94/NKG2A on lymphocytes, and by presenting a novel repertoire of immunogenic peptides, which recruits a subset of cytotoxic CD8+ T cells. Show less
Oliveira, C.C.; Veelen, P.A. van; Querido, B.; Ru, A. de; Sluijter, M.; Laban, S.; ... ; Hall, T. van 2010
The nonclassical major histocompatibility complex (MHC) Qa-1(b) accommodates monomorphic leader peptides and functions as a ligand for germ line receptors CD94/NKG2, which are expressed by natural... Show moreThe nonclassical major histocompatibility complex (MHC) Qa-1(b) accommodates monomorphic leader peptides and functions as a ligand for germ line receptors CD94/NKG2, which are expressed by natural killer cells and CD8(+) T cells. We here describe that the conserved peptides are replaced by a novel peptide repertoire of surprising diversity as a result of impairments in the antigen-processing pathway. This novel peptide repertoire represents immunogenic neoantigens for CD8(+) T cells, as we found that these Qa-1(b)-restricted T cells dominantly participated in the response to tumors with processing deficiencies. A surprisingly wide spectrum of target cells, irrespective of transformation status, MHC background, or type of processing deficiency, was recognized by this T cell subset, complying with the conserved nature of Qa-1(b). Target cell recognition depended on T cell receptor and Qa-1(b) interaction, and immunization with identified peptide epitopes demonstrated in vivo priming of CD8(+) T cells. Our data reveal that Qa-1(b), and most likely its human homologue human leukocyte antigen-E, is important for the defense against processing-deficient cells by displacing the monomorphic leader peptides, which relieves the inhibition through CD94/NKG2A on lymphocytes, and by presenting a novel repertoire of immunogenic peptides, which recruits a subset of cytotoxic CD8(+) T cells. Show less
