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Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity

Abstract

Whereas cancers grow within host tissues and evade host immunity through immune-editing and immunosuppression1,2,3,4,5, tumours are rarely transmissible between individuals. Much like transplanted allogeneic organs, allogeneic tumours are reliably rejected by host T cells, even when the tumour and host share the same major histocompatibility complex alleles, the most potent determinants of transplant rejection6,7,8,9,10. How such tumour-eradicating immunity is initiated remains unknown, although elucidating this process could provide the basis for inducing similar responses against naturally arising tumours. Here we find that allogeneic tumour rejection is initiated in mice by naturally occurring tumour-binding IgG antibodies, which enable dendritic cells (DCs) to internalize tumour antigens and subsequently activate tumour-reactive T cells. We exploited this mechanism to treat autologous and autochthonous tumours successfully. Either systemic administration of DCs loaded with allogeneic-IgG-coated tumour cells or intratumoral injection of allogeneic IgG in combination with DC stimuli induced potent T-cell-mediated antitumour immune responses, resulting in tumour eradication in mouse models of melanoma, pancreas, lung and breast cancer. Moreover, this strategy led to eradication of distant tumours and metastases, as well as the injected primary tumours. To assess the clinical relevance of these findings, we studied antibodies and cells from patients with lung cancer. T cells from these patients responded vigorously to autologous tumour antigens after culture with allogeneic-IgG-loaded DCs, recapitulating our findings in mice. These results reveal that tumour-binding allogeneic IgG can induce powerful antitumour immunity that can be exploited for cancer immunotherapy.

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Figure 1: Tumour-binding antibodies initiate rejection of allogeneic tumours.
Figure 2: AlloIgG-IC are internalized and presented by BMDCs and drive protective immunity in vivo.
Figure 3: TADCs, but not BMDCs, require stimulation to respond to alloIgG-IC.
Figure 4: Injection of tumours in situ with alloantibodies in combination with CD40 agonists and TNFα induces systemic DC-mediated antitumour immunity.

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Acknowledgements

We thank F. C. Grumet and N. E. Reticker-Flynn for helpful discussion. We also thank J. Sonnenburg for providing gnotobiotic mice. This work was supported by NIH grants U01 CA141468 and 5T32AI007290-27. M.H.S. is supported by NIH NRSA F31CA189331. I.L.L. is supported by a Smith Stanford Graduate Fellowship.

Author information

Authors and Affiliations

Authors

Contributions

Y.C. conceived the study, performed experiments and wrote the manuscript. M.H.S., I.L.L., T.R.P. and N.B. performed experiments, helped with experimental design and contributed to manuscript preparation. B.M.B. helped with experimental design, human tissue acquisition and manuscript preparation. N.P., M.G.D., J.A.K., E.S. and G.V.P. performed experiments. E.G.E. supervised the project, analysed data and wrote the manuscript.

Corresponding authors

Correspondence to Yaron Carmi or Edgar G. Engleman.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 DCs acquire an activated phenotype in response to allogeneic tumours injected in vivo, but not when co-cultured in vitro.

a, LMP (left) and B16 (right) growth in 129S1, C57BL/6, or allogeneic hosts pre-treated with anti-asialo-GM1 or anti-NK1.1 antibodies (n = 6, 3 independent experiments). Shown are representative plots of NK cells in the blood before tumour challenge. b, BrdU incorporation by CD4+ T cells (top) and CD8+ T cells (bottom) in lymphoid organs of 129S1 and C57BL/6 LMP-bearing mice (n = 8, 3 independent experiments). c, Representative flow cytometric analysis of CD11bhiLy6Chi myeloid cells and mature DCs (mDCs) on day 10 after C57BL/6 mice were inoculated with B16 tumour cells. d, Flow cytometric analysis of Ly6CCD11c+MHCII+ cells from LMP-bearing mice (left) and B16-bearing mice (right). Histograms show representative expression levels of co-stimulatory molecules on DCs from C57BL/6 and 129S1 mice (n = 8, 3 independent experiments). e, IL-12 (right) and TNFα (left) in the supernatants of syngeneic BMDCs, syngeneic blood monocyte-derived (Mo) DCs, allogeneic BMDCs or Mo-DCs incubated with live, frozen-thawed (necrotic), or mitomycin-C-treated (apoptotic) LMP cells or E. coli BioParticles overnight (n = 8, 4 independent experiments). Shown are the mean values ± s.e.m. *P < 0.05; **P < 0.01.

Extended Data Figure 2 Allogeneic hosts have a much higher titre of tumour-binding antibodies compared to syngeneic hosts

a, Flow cytometric analysis of the binding of various concentrations of IgG from 129S1, IgM from 129S1, IgG from C57BL/6 and IgM from C57BL/6 mice to LMP and B16 cells. The lower panel shows a representative histogram of IgG (left) or IgM (right) binding after incubation of 1 μg of C57BL/6 or 129S1 antibodies with 1 × 105 LMP (upper) or B16 (lower) cells (n = 8, 4 independent experiments). b, The left panel shows a representative histogram of the MFI of IgG after incubation of 2 μg of either control antibody (secondary Ab) or IgG from the serum of naive C57Bl/6 mice, B16-bearing C57BL/6 mice on day 7, B16-bearing C57BL/6 mice on day 14 or naive 129S1 mice with 1 × 105 B16 cells (n = 6, 4 independent experiments). Right graph shows MFI of the binding of 2 μg of each IgG to 1 × 105 B16 cells. c, Serum levels of IgG (left) and IgM (right) in C57BL/6 and 129S1 mice following i.p injection with anti-B220 and anti-CD19 antibodies (n = 8, 3 independent experiments). d, LMP tumour size in naive 129S1 mice injected with allogeneic IgG, allogeneic IgM, syngeneic IgG or syngeneic IgM on days −1 and 0 relative to tumour injection (n = 6, 3 independent experiments). Shown are the mean values ± s.e.m. *P < 0.05; **P < 0.01.

Extended Data Figure 3 Activation of BMDCs with immune complexes induces transferable T-cell immunity.

a, Mean levels of CD40 and CD86 expression (left) and IL-12 secretion (right) in BMDCs from C57BL/6 (WT) and FcγR KO mice activated with IgG-IC overnight (n = 6, 10 independent experiments). b, Proliferation of CD4+ T cells cultured with BMDCs from C57BL/6 and FcγR KO mice loaded with IgG-IC (n = 4, 5 independent experiments). c, Tumour recurrence in untreated mice, mice treated with WT BMDCs loaded with IgG-IC, or mice treated with FcγR KO BMDCs loaded with IgG-IC (n = 8, 3 independent experiments). d, e, Percentages of tumour-free mice after adoptive transfer of 5 × 106 splenic CD4+ T cells (left graph) or CD8+ T cells (right graph) from naive mice, or from LMP (d)- or B16 (e)-resected mice treated with DCs + IgGC57 IC, DCs + IgMC57 IC, DCs + IgG129 IC, or DCs + IgM129 IC, and subsequently challenged with LMP (d) or B16 (e) (n = 6, 3 independent experiments). Shown are the mean values ± s.e.m. **P < 0.01.

Extended Data Figure 4 Tumour-associated DCs do not respond to immune complexes.

a, Sorting and culture schema of DCs from BM and tumour. b, Mean levels of IL-12 (left) and TNFα (right) in the supernatants of DCs cultured overnight in medium alone, with B16 lysates, or with alloIgG-IC (n = 6, 4 independent experiments). c, Percentage of MHCII+CD86+ cells (left) or CFSE levels (right) in tumour-associated DCs after overnight activation with PBS or CFSE-labelled alloIgG-IC with or without stimulatory molecules (n = 12, 10 independent experiments). d, Representative flow cytometric analysis and confocal images from one out of three independent experiments of B16-derived DCs cultured overnight with CFSE-labelled fixed B16 cells (n = 8, 10 independent experiments). Shown are the mean values ± s.e.m. *P < 0.05; **P < 0.01.

Extended Data Figure 5 Tumour DCs from mice treated with alloIgG + adjuvant can internalize immune complexes and transfer immunity.

a, B16 tumour size in C57BL/6 mice left untreated or injected intratumorally with 129S1 allogeneic IgG, LPS, TNFα + CD28, LPS + allogeneic IgG or TNFα + CD28 + allogeneic IgG (n = 15, 3 independent experiments). b, B16 tumour size in C57BL/6 mice left untreated or injected intratumorally with 129S1 allogeneic IgG, TNFα, CD28, or CD40L (n = 12, 3 independent experiments). c, Lewis lung carcinoma (LL/2) tumour size in C57BL/6 mice left untreated, or injected intratumorally with 129S1 allogeneic IgG, TNFα + CD40L, TNFα + CD28, TNFα + CD40L + 129S1 allogeneic IgG or TNFα + CD28 + 129S1 IgG (n = 8, 2 independent experiments). d, Representative flow cytometric analysis from one out of three independent experiments of IgG binding total myeloid cells in B16 tumour-bearing mice 3 h after intratumoral injection of PBS or 5 μg PE-labelled allogeneic IgG. e, Total numbers of CD11c+ cells in the draining lymph nodes of B16 tumour-bearing mice 4 days after treatment (n = 6, 3 independent experiments). f, Gating and sorting strategy of immune cell populations infiltrating B16 tumours. g, B16 growth in mice vaccinated with 2 × 106 B cells, mast cells, macrophages or NK cells from B16 tumours untreated, or injected with allogeneic IgG or allogeneic IgG + TNFα + anti-CD40 (n = 6, 3 independent experiments). Shown are the mean values ± s.e.m. *P < 0.05; **P < 0.01.

Extended Data Figure 6 Allogeneic IgG recognises non-mutated cell membrane proteins on tumour cells.

a, B16 frequency in mice untreated, or treated with BMDCs loaded with intact B16 cells coated with allogeneic IgG, or with intact B16 cells cross-linked to syngeneic IgG (n = 8, 3 independent experiments). b, B16 tumour frequency in mice untreated or treated with BMDCs loaded with intact B16 cells coated with allogeneic IgG or with intact B16 coated with monoclonal IgG against MHC-I (n = 8, 3 independent experiments). c, RMA tumour growth following inoculation with 2.5 × 105 tumour cells in naive C57BL/6 mice, or in C57BL/6 mice in which B16 tumours had completely regressed after treatment with allogeneic IgG + TNFα + anti-CD40. Also shown is the lack of B16 tumour growth in C57BL/6 mice that were re-challenged with 2 × 105 B16 tumour cells following the regression of this tumour after treatment with allogeneic IgG + TNFα + anti-CD40 (n = 8, 2 independent experiments). d, Left: tumour frequency in mice untreated or treated with DCs loaded with immune complexes formed with allogeneic IgG and cytosolic tumour proteins, nuclear tumour proteins or membrane tumour proteins. Right: tumour frequency in mice untreated, treated with DCs loaded with immune complexes formed from allogeneic IgG and membrane proteins, membrane proteins without O- and N-glycans, or heat-denatured membrane proteins (n = 5, 3 independent experiments). e, B16 tumour growth in C57BL/6 mice untreated, or injected with TNFα + anti-CD40, TNFα + anti-CD40 + allogeneic IgG, or TNFα + anti-CD40 and allogeneic IgG absorbed on normal cells of the IgG-donor background (blue diamonds) or on normal cells of the tumour background (green squares) (n = 6, 3 independent experiments). f, Tumour recurrence rates after resection in mice left untreated, treated with 2 × 106 DCs loaded with IgG-IC from conventionally raised C57BL/6, or with 2 × 106 DCs loaded with IgG-IC from gnotobiotic C57BL/6 mice (n = 6, 2 independent experiments). Shown are the mean values ± s.e.m. *P < 0.05; **P < 0.01.

Extended Data Figure 7 Allogeneic hosts have a higher titre of anti-GP-NMB IgG, which can be used to induce tumour immunity.

a, Representative flow cytometric analysis and quantification of binding of anti-IgG secondary antibody alone, 1 μg anti-GPNMB or 2 μg GPNMB per 1 × 105 B16 cells, normal skin cells, or normal spleen cells (n = 6, 3 independent experiments). b, Percentage of MHCII+CD86+ BMDCs following overnight activation with untreated LMP or B16 tumour cells, or with tumour cells coated with anti-GPNMB (2 μg per 1 × 105 tumour cells) (n = 8, 3 independent experiments). c, Western blot of recombinant GPNMB (62.5 ng and 125 ng) performed with 10 μg ml−1 of IgG from naive 129S1 mice, naive C57BL/6 mice, or 1 μg ml−1 anti-GPNMB (2 independent experiments). d, B16 tumour size in mice untreated or treated with TNFα + anti-CD40, allogeneic IgG, anti-GPNMB IgG, TNFα + anti-CD40 + allogeneic IgG, or with TNFα + anti-CD40 + anti-GPNMB (n = 8, 3 independent experiments). e, B16 tumour size in C57Bl/6 WT mice untreated or treated with TNFα + anti-CD40, TNFα + anti-CD40 + allogeneic IgG, or with TNFα + anti-CD40 + anti-GPNMB, or in FcγR KO mice treated with TNFα + anti-CD40 + allogeneic IgG, or with TNFα + anti-CD40 + anti-GPNMB (n = 8, 3 independent experiments). Shown are the mean values ± s.e.m. *P < 0.05; **P < 0.01.

Extended Data Figure 8 AlloIgG and anti-GPNMB IgG induce tumour-reactive T-cell infiltration and activation.

a, Representative flow cytometry plots of CD4+ and CD8+ cells in B16 tumours 6 days after treatment. Left: percentage of CD45+ cells infiltrating B16 tumours 15–17 days after s.c. inoculation or 6 days after treatment. Right: percentage of CD4+ and CD8+ cells among tumour-infiltrating CD45+ cells (n = 10, 3 independent experiments). b, Percentages of CD44 and IFNγ co-expressing CD4+ and CD8+ cells among tumour-infiltrating CD45+ cells 6 days after treatment or 15 days following s.c. inoculation (n = 10, 3 independent experiments) c, Frequency of IFNγ-expressing T cells that recognize gp100 and Trp2 among day 6 post-treatment tumour-infiltrating CD8+ cells. Gate shown: CD8+ T cells (n = 10, 3 independent experiments). d, Percentage of tumour-free mice following adoptive transfer of T cells from day 6 post-treatment B16 tumour-bearing mice untreated, treated with TNFα + anti-CD40, with TNFα + anti-CD40 + allogeneic IgG, or with TNFα + anti-CD40 + anti-GPNMB (n = 9, 3 independent experiments). e, Upper left: B16 tumour growth in untreated C57BL/6 mice injected with rat IgG, with rat anti-CD4, or with rat-CD8. Upper right: B16 tumour growth in C57BL/6 mice treated with TNFα + anti-CD40 and injected with rat IgG, with rat anti-CD4, or with rat-CD8. Lower left: B16 growth in C57BL/6 mice treated with TNFα + anti-CD40 + allogeneic IgG and injected with rat IgG, with rat anti-CD4, or with rat-CD8. Lower right: B16 growth in C57BL/6 mice treated with TNFα + anti-CD40 + anti-GPNMB and injected with rat IgG, with rat anti-CD4, or with rat-CD8 (n = 9, 3 independent experiments). Shown are the mean values ± s.e.m. from three independent experiments. *P < 0.05; **P < 0.01.

Extended Data Figure 9 AlloIgG can activate human tumour DCs to process autologous tumour cells.

a, Representative haematoxylin and eosin sections of lung metastases on day 30 from one out of three independent experiments performed (original magnification, 10×). b, MFI of tumour cells from MSTO-resected patients coated with autologous IgG or IgG from healthy donors (n = 2 in technical triplicates). c, d, Wide-field microscopy (c) and flow cytometry plots (d) of TADCs from a lung carcinoma patient incubated overnight with autologous CFSE-labelled tumour cells (green) coated with self IgG or allogeneic IgG derived from a pool of 10 donors (1 μg per 2 × 105 cells) and in the presence of 50 ng ml−1 TNFα and 1 μg ml−1 CD40L (n = 2 in technical triplicates). Shown are the mean values ± s.e.m. from two independent experiments. *P < 0.05; **P < 0.01.

Extended Data Table 1 Allogeneic IgG binds numerous membrane tumour proteins

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Carmi, Y., Spitzer, M., Linde, I. et al. Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity. Nature 521, 99–104 (2015). https://doi.org/10.1038/nature14424

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