Adoptive cell therapies using genetically engineered T cell receptor or chimeric antigen receptor T cells are emerging forms of immunotherapy that redirect T cells to specifically target cancer. However, tumor antigen heterogeneity remains a key challenge limiting their efficacy against solid cancers. Here, we engineered T cells to secrete the dendritic cell (DC) growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L-secreting T cells expanded intratumoral conventional type 1 DCs and substantially increased host DC and T cell activation when combined with immune agonists poly (I:C) and anti-4-1BB. Importantly, combination therapy led to enhanced inhibition of tumor growth and the induction of epitope spreading towards antigens beyond those recognized by adoptively transferred T cells in solid tumor models of T cell receptor and chimeric antigen receptor T cell therapy. Our data suggest that augmenting endogenous DCs is a promising strategy to overcome the clinical problem of antigen-negative tumor escape following adoptive cell therapy.
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The data generated or analyzed to support the findings of this study are available in this article and from the corresponding author upon request without restrictions. Source data for Figs. 1–7 and Extended Data Figs. 1–9 are presented with the paper.
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We acknowledge assistance from the staff of the Animal Facility, the Centre for Advanced Histology and Microscopy, the Flow Cytometry Facility, the Molecular Genomics Core and the Pathology departments at the Peter MacCallum Cancer Centre. We also acknowledge the contribution of consumer advocates K. Gill, M. Rear and G. Sissing for this study. This work was funded by the National Health and Medical Research Council (NHMRC; grant nos. 1062580, 1143976 and 1150425), the Cancer Council Victoria (grant no. 1156382), the National Breast Cancer Foundation (grant no. IIRS-19-016 19-22), the CLEARbridge Foundation and the Tour de Cure Foundation. P.A.B. is supported by a National Breast Cancer Foundation Fellowship (ID no. ECF-17-005). P.K.D., A.M.L. and K.K. are supported by NHMRC Research Fellowships (grant nos. APP1041828, APP1080321 and APP1102792, respectively).
P.A.B. and P.K.D. are inventors on a patent filed for the following study (filing no. PCT/AU2019/050660).
Peer review information Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
a, Flt3L levels from 24JK-Her2 and MC38 cell lines transduced to express Cherry control (Cherry) or Flt3L Cherry (Cherry FL). Data represent technical replicates from one of two independent experiments with similar results. b, Tumor and serum Flt3L levels from hHer2 mice 6 days post inoculation with 24JK-Her2 Cherry or Cherry FL cells (3 mice/group), from one of two independent experiments. c, Tumor measurement (2-way ANOVA) and survival (tumor area > 100mm2) of C57BL/6 mice subcutaneously injected with 5 × 104 MC38 expressing Flt3L cherry (Cherry FL, n = 7) or cherry control (Cherry, n = 8) (two-tailed Mantel-Cox, two pooled independent experiments). d, Tumor myeloid cell gating strategy. Lineage markers include Thy1.2, CD19, B220/CD45R, NK1.1 and Ly6G. e, Frequency of tumor infiltrating CD4+ T cells, Treg, CD11b+ cDC2, macrophages and neutrophils 9 days post tumor inoculation with 24JK-Her2 Cherry FL or control. Bars represent mean ± SEM, b, e Unpaired Student’s t-test, symbols represent individual mice.
a, In vitro differentiated BM DC gating strategy. b, Contour plots of BM cells differentiated with (FL-DCs) or without (GM-DCs) exogenous Flt3L (20 ng/mL). c, IFN-γ and TNF levels in supernatants of 4 × 104 naive OT-I T cells co-cultured for 5 days with OVA257-264 peptide (0.1 μg/mL) pulsed GM- or FL-DCs at a 2:1 ratio. Where indicated, DCs were activated with poly (I:C) (25 μg/mL) for 24 hours prior to co-culture. Bars represent mean ± SEM of technical triplicates from one of three independent experiments with similar results. d, Schematic illustration of OT-I T cell transduction and preconditioning with cytokines IL-7 and IL-15 (IL-7/15).
Extended Data Fig. 3 Preconditioning regimens for lymphodepletion and cDC1 expansion following OT-I FL therapy.
a, Analysis of splenic immune cell subsets 2 days after total body irradiation (TBI), representative of one of two independent experiments with similar results. b, Fold change of immune cell subsets normalized to control non-irradiated mice. c, Comparison of splenic immune cell subsets after preconditioning with titrated doses of TBI or cyclophosphamide (CP). d, Fold change of immune cell subsets after 0.5 Gy TBI or 50 mg/kg CP normalized to control mice. e, hHer2 mice were irradiated at indicated doses and subcutaneously inoculated with 5 × 105 Flt3L expressing 24JK-Her2 cells (n = 6 mice/group), from of one of two independent experiments (2-way ANOVA). f–g, Absolute numbers of BM pre-cDC, pre-cDC1 and pre-cDC2 per femur, and splenic cDC1 and cDC2 populations 7 days post adoptive transfer, after preconditioning with 0.5 Gy TBI or 50 mg/kg CP. Bars represent mean ± SEM, a, f, g 1-way ANOVA, symbols represent individual mice.
Extended Data Fig. 4 Flt3L-secreting T cells promote DC proliferation and tumor infiltration of endogenous CD8+ T cells. Related to Fig. 3.
a, BM pre-cDC gating strategy. Lineage markers include Thy1.2, CD19, and NK1.1. b, Frequency of pre-cDC1 and pre-cDC2 as a percentage of total BM pre-cDC (NT n = 4 mice, OT-I and FL n = 6 mice/group). c, Absolute numbers of macrophages and neutrophils per mg of tumor, and d, Frequency of tumor cDC1, cDC2 and cDC1 precursors as a percentage of total tumor DCs post adoptive transfer (NT n = 4, OT-1 n = 6, FL n = 5). e, Adoptive transfer of E0771-OVA tumor-bearing mice with 2 × 107 antigen-specific OT-I T cells or antigen non-specific pmel-1 T cells transduced to secrete Flt3L (OT-I FL and pmel-1 FL, respectively). (Left) Expression of surface NGFR marker in OT-I FL and pmel-1 FL cells. (Mid) Flt3L from tumor supernatants (day 7). (Right) Absolute numbers of tumor cDC1 and cDC1 precursors on day 7 post adoptive transfer with OT-I FL or pmel-1 FL. f, Representative contour plots of tumor cDC1 and cDC2 respectively secreting IL-12 and TNF. g, Absolute numbers of migratory and resident dLN DCs (day 5 NT n = 4 mice, OT-I n = 6, FL n = 5; day 7 NT and FL n = 8/group, OT-I n = 11) and h, splenic cDC1, cDC2, macrophages and neutrophils (NT n = 3 – 4/group, OT-I n = 6/group, FL = 5 – 6/group). Bars represent mean ± SEM, b–e, g, h 1-way ANOVA, a–g Data representative of one of two independent experiments with similar results, d,e Symbols represent individual mice.
a, Absolute numbers of Treg per mg tumor on day 7 post adoptive transfer (1-way ANOVA), from one of two independent experiments. b, Frequency of CD62L+TCF-1+ OT-I or endogenous CD8+ T cells in the tumor on day 7 post adoptive transfer from two pooled independent experiments (unpaired Student’s t-test). Symbols represent individual mice.
a, Activated BM DCs were pulsed with OVA257-264 before co-culture with naive OT-I T cells (1:2). Frequencies of CD69+ and 4-1BB+ CD8+ OT-I T cells day 5 post co-culture, data represent technical triplicates from one of three independent experiments with similar results. b, Survival (tumor area > 100mm2) from one of two independent experiments (two-tailed Mantel-Cox) of mice subcutaneously inoculated with 5 × 105 MC38 Cherry FL cells or control. Ten days later, mice were injected with poly (I:C:) (200 μg) and/or anti-4-1BB (100 μg). Subsequent poly (I:C) were administered on days 4 and 8 post initial treatment. c, E0771-OVA tumor bearing C57BL/6 WT mice were treated accordingly with OT-I FL, poly (I:C), anti-4-1BB (top; NT and FL + anti-4-1BB n = 5 mice/group, rest n = 4/group; 2-way ANOVA) or adjuvants with no T cells (bottom; n = 5 mice/group). Arrows (top) indicate adjuvants (days 5 and 8). Data points from NT, OT-I FL and OT-I FL + poly (I:C) + anti-4-1BB were included in Fig. 4c pooled data. d, Significantly upregulated genes based on GO term ‘Response to type I Interferon’ (GO: 0034340) (day 6). e, Representative CD40+CD86+ activated DCs (day 7). f–g, Absolute numbers of PMA and ionomycin stimulated, IFN-γ-producing CD8+ T cells on day 7 post adoptive transfer from 2 – 4 pooled independent experiments, symbols represent individual mice, 1-way ANOVA. h, hHer2 mice were subcutaneously injected with 1 × 106 MC38-Her2, preconditioned and treated with 1 × 107 CAR T or CAR T FL cells on days 5 and 6 post tumor inoculation (NT and FL n = 5 mice/group, CAR T n = 6, CAR T + adjuvants n = 12, FL + adjuvants n = 13, 2-way ANOVA, Sidak’s multiple comparison). Arrow indicate adjuvants on day 5 post adoptive transfer. a, c, f–h Bars represent mean ± SEM.
a, Frequency of mCherry+ CD4+ and CD8+ CAR T cells from bulk transduced CAR T cell population prior to adoptive transfer, from two pooled independent experiments with n = 2 technical replicates per experiment. b, Frequency of CD4+ and CD8+ mCherry+ CAR T cells in the dLN of E0771-OVA-Her2 tumor-bearing mice on 7 days post adoptive transfer (CAR n = 8 mice, FL n = 9, CAR T + adjuvants n = 12, FL + adjuvants n = 12). Bars represent mean ± SEM.
hHer2 transgenic mice were inoculated with 4 × 105 E0771-OVA-Her2 tumor cells and treated with transduced CAR T cells as per Fig. 6f. Mice were monitored for changes in weight. Alternatively, sera and organs were assessed at 48 hours post adjuvant therapy for toxicity studies. a, Liver function and/or damage was assessed by serum alanine transaminase (ALT), aspartate aminotransferase (AST), total albumin, bilirubin, and gamma glutamyl transferase (GGT) levels. b, Kidney function and/or damage was assessed by serum urea and creatinine levels. c, Sera were assessed for levels of IFN-γ, IL-1β, IL-6, GM-CSF, G-CSF, MCP-1 and TNF cytokines. d, Percentage weight change relative to day 0 measurements. Dotted line (90%) indicates the maximum ethical limit allowed for weight reduction. Arrows indicate adjuvant administration (NT n = 5 mice, CAR T and FL + Isotype n = 6 mice/group, CAR T and FL + adjuvants n = 8/group). e, Representative hematoxylin and eosin histology staining of cerebellum, liver, kidney, lung and spleen of control non-treated (NT), CAR T or CAR T FL adjuvant treated mice (3 mice/group). f, Sera were assessed for antinuclear antibodies as an indication of autoimmunity (n = 5 mice/group). Sera from NZB/W (with proteinuria; n = 3) and C57BL/6 mice (n = 3) immunized with an irrelevant antigen (NP-KLH) were respectively used as positive and negative controls. Bars represent mean ± SEM, a–c Symbols represent individual mice, 1-way ANOVA.
a, Gating strategy for BM populations. b, Absolute numbers of hematopoietic stem cells (HSC), common lymphoid progenitors (CLP), common dendritic progenitors (CDP) and myeloid and dendritic progenitors (MDP) in the BM from E0771-OVA tumor-bearing mice 7 or 14 days post adoptive transfer with Flt3L-secreting OT-I T cells. Data shown as mean ± SEM of n = 5 mice/group, 1-way ANOVA.
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Lai, J., Mardiana, S., House, I.G. et al. Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity. Nat Immunol 21, 914–926 (2020). https://doi.org/10.1038/s41590-020-0676-7
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