Modeling the specific CD4+ T cell response against a tumor neoantigen.
The antitumor activity of CD4(+) T cells is increasingly acknowledged in both humans and mice. The involved mechanisms have been mostly studied using transplanted tumor mouse systems. In these models, many tumor cells die at the time of implantation leading to the release of Ag in an inflammatory context contrasting with the slow and nondestructive growth of early-stage human tumors. In this study, we show that the presentation of a MHC class II-restricted model Ag (male, DBY) released by dying tumor cells may last more than 4 wk. The duration of Ag presentation varies according to the way the cells are killed before implantation. To avoid this artifactual early priming of the host precluding the study of the interactions between the immune system and tumors at the steady state, we generated a cell line expressing the DBY Ag in an inducible manner. Ag expression can be efficiently induced in vivo several days after tumor implantation. We show that the Ag reaches the lymph node and activates naive CD4(+) T cells to proliferate and recirculate. We did not observe de novo induction of tumor-specific regulatory T cells. However, we observed Th1/Th17 effector cells in the tumor draining lymph node and tumors. Thus, when a neoantigen appears in established tumors, the immune system is not ignorant and naive CD4(+) T cells are not tolerized. This opens up the possibility of therapeutic vaccines improving the immune response toward tumor-specific neoantigens.
INSERM U932, Institut Curie, 75005 Paris, France;
Héloïse
H
Flament
INSERM U932, Institut Curie, 75005 Paris, France;
Ruby
R
Alonso Ramirez
INSERM U932, Institut Curie, 75005 Paris, France;
Virginie
V
Prémel
INSERM U932, Institut Curie, 75005 Paris, France;
Nathalie T
NT
Joncker
INSERM U932, Institut Curie, 75005 Paris, France;
Alexandra
A
Jacquet
Center of Clinical Investigations in Biotherapy 1428 (Institut Gustave Roussy/Curie), Institut Curie, 75005 Paris, France; and Department of Medical Oncology, Institut Curie, 75005 Paris, France.
Suzy
S
Scholl
INSERM U932, Institut Curie, 75005 Paris, France; Center of Clinical Investigations in Biotherapy 1428 (Institut Gustave Roussy/Curie), Institut Curie, 75005 Paris, France; and olivier.lantz@curie.fr.
Olivier
O
Lantz
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000276:immunology; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D010641:Phenotype
D000951:Antigens, Neoplasm; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D015778:Minor Histocompatibility Antigens; D010446:Peptide Fragments; C492034:DDX3Y protein, human; D053487:DEAD-box RNA Helicases