CCL5-mediated endogenous antitumor immunity elicited by adoptively transferred lymphocytes and dendritic cell depletion.
Adoptive transfer of antitumor T cells is a promisingly effective therapy for various cancers, but its effect on endogenous antitumor immune mechanisms remains largely unknown. Here, we show that the administration of naive T cells de novo primed for only 7 days against tumor antigens resulted in the durable rejection of otherwise lethal ovarian cancers when coupled with the depletion of tumor-associated immunosuppressive dendritic cells (DC). Therapeutic activity required tumor antigen specificity and perforin expression by the adoptively transferred T cells, but not IFN-gamma production. Importantly, these shortly primed T cells secreted large amounts of CCL5, which was required for their therapeutic benefit. Accordingly, transferred T cells recruited CCR5(+) DCs into the tumor, where they showed distinct immunostimulatory attributes. Activated CCR5(+) host T cells with antitumor activity also accumulated at tumor locations, and endogenous tumor-specific memory T cells remained elevated after the disappearance of transferred lymphocytes. Therefore, persistent, long-lived antitumor immunity was triggered by the administration of ex vivo activated T cells, but was directly mediated by immune cells of host origin. Our data unveil a CCL5-dependent mechanism of awakening endogenous antitumor immunity triggered by ex vivo expanded T cells, which is augmented by tumor-specific targeting of the cancer microenvironment.
Nesbeth
Yolanda
Y
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire, USA.
Scarlett
Uciane
U
Cubillos-Ruiz
Juan
J
Martinez
Diana
D
Engle
Xavier
X
Turk
Mary-Jo
MJ
Conejo-Garcia
Jose R
JR
D000818:Animals; D039521:CD11c Antigen / Q000276:immunology; D018946:Chemokine CCL5 / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D053804:Granzymes / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*
C483024:CCL5 protein, human; D039521:CD11c Antigen; D018946:Chemokine CCL5; D007371:Interferon-gamma; D053804:Granzymes