RESUMEN
The therapeutic efficacy of anthracyclines relies on antitumor immune responses elicited by dying cancer cells. How chemotherapy-induced cell death leads to efficient antigen presentation to T cells, however, remains a conundrum. We found that intratumoral CD11c(+)CD11b(+)Ly6C(hi) cells, which displayed some characteristics of inflammatory dendritic cells and included granulomonocytic precursors, were crucial for anthracycline-induced anticancer immune responses. ATP released by dying cancer cells recruited myeloid cells into tumors and stimulated the local differentiation of CD11c(+)CD11b(+)Ly6C(hi) cells. Such cells efficiently engulfed tumor antigens in situ and presented them to T lymphocytes, thus vaccinating mice, upon adoptive transfer, against a challenge with cancer cells. Manipulations preventing tumor infiltration by CD11c(+)CD11b(+)Ly6C(hi) cells, such as the local overexpression of ectonucleotidases, the blockade of purinergic receptors, or the neutralization of CD11b, abolished the immune system-dependent antitumor activity of anthracyclines. Our results identify a subset of tumor-infiltrating leukocytes as therapy-relevant antigen-presenting cells.
Asunto(s)
Antraciclinas/administración & dosificación , Células Presentadoras de Antígenos/inmunología , Antineoplásicos/administración & dosificación , Células Dendríticas/inmunología , Neoplasias Experimentales/inmunología , Traslado Adoptivo , Animales , Antraciclinas/efectos adversos , Antígenos Ly/metabolismo , Antígenos de Neoplasias/inmunología , Antineoplásicos/efectos adversos , Apoptosis , Antígeno CD11b/metabolismo , Antígeno CD11c/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Células Precursoras de Granulocitos/inmunología , Inmunidad Celular , Ratones , Ratones Endogámicos C57BL , Células Precursoras de Monocitos y Macrófagos/inmunología , Neoplasias Experimentales/tratamiento farmacológico , Nucleotidasas/metabolismo , Receptores Purinérgicos/metabolismoRESUMEN
Immunomodulators are effective in controlling hematologic malignancy by initiating or reactivating host antitumor immunity to otherwise poorly immunogenic and immune suppressive cancers. We aimed to boost antitumor immunity in B-cell lymphoma by developing a tumor cell vaccine incorporating α-galactosylceramide (α-GalCer) that targets the immune adjuvant properties of NKT cells. In the Eµ-myc transgenic mouse model, single therapeutic vaccination of irradiated, α-GalCer-loaded autologous tumor cells was sufficient to significantly inhibit growth of established tumors and prolong survival. Vaccine-induced antilymphoma immunity required NKT cells, NK cells, and CD8 T cells, and early IL-12-dependent production of IFN-γ. CD4 T cells, gamma/delta T cells, and IL-18 were not critical. Vaccine treatment induced a large systemic spike of IFN-γ and transient peripheral expansion of both NKT cells and NK cells, the major sources of IFN-γ. Furthermore, this vaccine approach was assessed in several other hematopoietic tumor models and was also therapeutically effective against AML-ETO9a acute myeloid leukemia. Replacing α-GalCer with ß-mannosylceramide resulted in prolonged protection against Eµ-myc lymphoma. Overall, our results demonstrate a potent immune adjuvant effect of NKT cell ligands in therapeutic anticancer vaccination against oncogene-driven lymphomas, and this work supports clinical investigation of NKT cell-based immunotherapy in patients with hematologic malignancies.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Galactosilceramidas/administración & dosificación , Genes myc/genética , Inmunoterapia , Linfoma de Células B/inmunología , Linfoma de Células B/prevención & control , Células T Asesinas Naturales/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Animales , Citotoxicidad Inmunológica/inmunología , Femenino , Citometría de Flujo , Genes Codificadores de la Cadena delta de los Receptores de Linfocito T/fisiología , Humanos , Interferón gamma/metabolismo , Interleucina-12/fisiología , Interleucina-18/fisiología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Linfoma de Células B/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Células T Asesinas Naturales/metabolismo , Células T Asesinas Naturales/patología , VacunaciónRESUMEN
The natural killer T (NKT) cell ligand, alpha-galactosylceramide (α-GalCer), represents a potential adjuvant to boost immunotherapeutic vaccination strategies against poorly immunogenic cancers. The objective of this study was to assess the therapeutic potential of an α-GalCer-loaded tumor-cell vaccine against solid tumors in mice and to enhance the effectiveness of this approach by removing immune suppression associated with the activity of Foxp3(+) regulatory T cells (Tregs). In the B16F10 melanoma model, we show that single vaccination with irradiated, α-GalCer-loaded tumor cells resulted in suppression of established subcutaneous (s.c.) B16F10 tumor growth, which was mediated by NKT cell-dependent IFN-γ production and enhanced in the absence of IL-17 A. Selective depletion of Foxp3(+) Tregs in transgenic DEpletion of REGulatory T cells (DEREG) mice led to significant inhibition of B16F10 tumor growth and enhanced survival of mice receiving vaccination. Short-term elimination of Foxp3(+) Tregs (<7 days) was sufficient to boost vaccine-induced immunity. Enhanced antitumor activity with combination therapy was associated with an increase in systemic NK cell and effector CD8(+) T-cell activation and IFN-γ production, as well as infiltration of effector CD8(+) T cells into the tumor. Overall, these findings demonstrate that transient depletion of Foxp3(+) Tregs constitutes a highly effective strategy to improve the therapeutic efficacy of anticancer vaccination with NKT cell adjuvants.