ABSTRACT
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.
Subject(s)
Anthracyclines/administration & dosage , Antigen-Presenting Cells/immunology , Antineoplastic Agents/administration & dosage , Dendritic Cells/immunology , Neoplasms, Experimental/immunology , Adoptive Transfer , Animals , Anthracyclines/adverse effects , Antigens, Ly/metabolism , Antigens, Neoplasm/immunology , Antineoplastic Agents/adverse effects , Apoptosis , CD11b Antigen/metabolism , CD11c Antigen/metabolism , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Granulocyte Precursor Cells/immunology , Immunity, Cellular , Mice , Mice, Inbred C57BL , Monocyte-Macrophage Precursor Cells/immunology , Neoplasms, Experimental/drug therapy , Nucleotidases/metabolism , Receptors, Purinergic/metabolismABSTRACT
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.
Subject(s)
Cancer Vaccines/therapeutic use , Galactosylceramides/administration & dosage , Genes, myc/genetics , Immunotherapy , Lymphoma, B-Cell/immunology , Lymphoma, B-Cell/prevention & control , Natural Killer T-Cells/immunology , Adjuvants, Immunologic/administration & dosage , Animals , Cytotoxicity, Immunologic/immunology , Female , Flow Cytometry , Genes, T-Cell Receptor delta/physiology , Humans , Interferon-gamma/metabolism , Interleukin-12/physiology , Interleukin-18/physiology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Killer Cells, Natural/pathology , Lymphoma, B-Cell/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Natural Killer T-Cells/metabolism , Natural Killer T-Cells/pathology , VaccinationABSTRACT
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.