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Gasdermin E suppresses tumour growth by activating anti-tumour immunity

Abstract

Cleavage of the gasdermin proteins to produce pore-forming amino-terminal fragments causes inflammatory cell death (pyroptosis)1. Gasdermin E (GSDME, also known as DFNA5)—mutated in familial ageing-related hearing loss2—can be cleaved by caspase 3, thereby converting noninflammatory apoptosis to pyroptosis in GSDME-expressing cells3,4,5. GSDME expression is suppressed in many cancers, and reduced GSDME levels are associated with decreased survival as a result of breast cancer2,6, suggesting that GSDME might be a tumour suppressor. Here we show that 20 of 22 tested cancer-associated GSDME mutations reduce GSDME function. In mice, knocking out Gsdme in GSDME-expressing tumours enhances, whereas ectopic expression in Gsdme-repressed tumours inhibits, tumour growth. This tumour suppression is mediated by killer cytotoxic lymphocytes: it is abrogated in perforin-deficient mice or mice depleted of killer lymphocytes. GSDME expression enhances the phagocytosis of tumour cells by tumour-associated macrophages, as well as the number and functions of tumour-infiltrating natural-killer and CD8+ T lymphocytes. Killer-cell granzyme B also activates caspase-independent pyroptosis in target cells by directly cleaving GSDME at the same site as caspase 3. Uncleavable or pore-defective GSDME proteins are not tumour suppressive. Thus, tumour GSDME acts as a tumour suppressor by activating pyroptosis, enhancing anti-tumour immunity.

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Fig. 1: Ectopic expression of pore-forming, but not inactive, GSDME reduces tumour growth and enhances tumour immune responses.
Fig. 2: GSDME-mediated tumour inhibition depends on cytotoxic lymphocytes.
Fig. 3: Killer cells cleave GSDME and induce GSDME-dependent pyroptosis in target cells.
Fig. 4: GzmB directly cleaves GSDME to cause pyroptosis.

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Data availability

All relevant data are available in the Source Data (for Figs. 14 and Extended Data Figs. 111) or Supplementary Information associated with this paper.

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Acknowledgements

We thank the US National Institutes of Health (NIH) Tetramer Core Facility for providing the eGFP tetramer. This work was supported by NIH grant R01 AI139914 (to H.W. and J.L.), a Charles A. King Trust Fellowship (to Z.Z.) and a Department of Defense Breast Cancer Breakthrough Fellowship Award (to Y.Z.). The mutations in GSDME primary tumours and primary human breast cancer and colorectal cancer expression analyses in this study are based upon data generated by The Cancer Genome Atlas (TCGA) Research Network (https://www.cancer.gov/tcga).

Author information

Authors and Affiliations

Authors

Contributions

Z.Z. conceived the study. Z.Z., Y.Z. and J.L. designed experiments and analysed data. Z.Z. and Y.Z. performed the majority of the experiments, assisted by S.X., Q.K., S.L., X.L., C.J., K.F.M.-S., T.M.Y.M. and J.A. S.S., Y.Y. and H.W. analysed the locations of GSDME mutations, helped to prepare recombinant proteins and provided valuable comments. J.L., Z.Z. and Y.Z. wrote the manuscript.

Corresponding authors

Correspondence to Zhibin Zhang or Judy Lieberman.

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The authors declare no competing interests.

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Peer review informationNature thanks Ed Mocarski, Dmitri V. Krysko and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 GSDME expression in human and mouse tumour cell lines.

a, b, Gsdme messenger RNA (a) and protein (b) levels in the indicated mouse cancer cell lines, assessed by qPCR, relative to Gapdh (a), and by immunoblot (b). c, GSDME expression relative to GAPDH in normal tissue and tumours from breast invasive carcinoma (BRCA) and colon adenocarcinoma (COAD) patients from TCGA, compared with the qRT–PCR values for mouse cancer cell lines used here. P values comparing normal tissue and cancer tissues were calculated using unpaired two-tailed Student’s t-test. d, f, Expression of mGSDME in EMT6 (d) and CT26 (f) clones knocked out for Gsdme, or in control (Ctl) cells treated with nontargeting vector, assessed by immunoblot for GSDME. Actin serves as a loading control. e, g, Cell proliferation determined by CellTiter 96 in EMT6 (e) or CT26 (g) control and Gsdme knockout cells (n = 6 samples per group). h, Expression of hGSDME in SH-SY5Y clones knocked out for GSDME or in control cells treated with nontargeting vector, assessed by immunoblot for GSDME. i, j, Expression of mGSDME in GSDME-overexpressing (OE) and empty-vector-transduced B16 (i) or 4T1E (j) cells, assessed by immunoblot. k, Expression of hGSDME in GSDME-overexpressing and empty-vector-transduced HeLa cells, assessed by immunoblot. Differences among multiple groups in e, g were analysed by one-way ANOVA, using the Holm–Sidak method for multiple comparisons. P values in e, g compare knockout and control cells. ***P < 0.0001. Data are mean ± s.d. of three technical (a) or six biological (e, g) replicates. Data are representative of at least two independent experiments.

Source data

Extended Data Fig. 2 Raptinal and/or TRAIL induces pyroptosis in B16 and HeLa cells overexpressing GSDME.

ae, Comparison of cell death after adding raptinal to empty vector and mGSDME-overexpressing B16 cells. a, Kinetics of overall cell death, assayed by counting annexin-V-positive and/or PI-positive cells by flow cytometry. b, c, Pyroptosis assessed by SYTOX green uptake (b) and LDH release (c). d, Time-lapse microscopy images showing morphological changes and SYTOX green uptake. e, Kinetics of caspase 3 and GSDME cleavage and HMGB1 release by immunoblot of cell lysates and culture supernatants. f, g, SYTOX green uptake assessed by plate reader (f) and time-lapse confocal microscopy (g) after treatment of empty vector and hGSDME-overexpressing HeLa cells with raptinal. h, i, TRAIL-mediated induction of cell death at 16 h post treatment, assessed by CellTiter-Glo (h), and LDH release in HeLa cells transduced with an empty vector or in hGSDME-overexpressing HeLa cells in the presence or absence of the pan-caspase inhibitor zVAD-fmk (i). UNT, untreated. The areas under the curve in ac, f and data in h, i were compared by two-tailed Student’s t-test. Data are means ± s.d. of biological triplicate wells. ***P < 0.0001. Scale bar, 20 μm. Data are representative of two independent experiments.

Source data

Extended Data Fig. 3 GSDME mutations in tumours are mostly LOF.

a, GSDME N-terminal (NT) mutations in primary cancer cells in TCGA (https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga). Asterisks denote stop codons; red, truncations; blue, mutants analysed here. bg, Seventeen GSDME-NT cancer-associated mutations are mapped onto GSDME-NT (amino acids 1–241)—modelled here on the basis of the cryo-electron microscopy structure of the pore conformation of the GSDMA3-NT (Protein DataBank identification code 6CB8)8. These mutations were analysed in two arbitrarily assigned groups (b, e). These 17 mutations and the E245K mutation were analysed, after transient expression of wild-type Flag-tagged GSDME (WT FL GSDME) or wild-type or mutated GSDME-NT (amino acids 1–270) in HEK293T cells, for GSDME expression by immunoblot (c, f) and for LDH release by CytoTox 96 assay (d, g). hl, Effect of four cancer-related GSDME truncation mutations (resulting in shortened proteins comprising amino acids 1–46, 1–210, 1–451 and 1–491) on GSDME-mediated cell death. GSDME expression of truncated proteins or FL or GSDME-NT (1–270) in HEK293T cells (h, k) and their effect on HEK293T cell death, assessed by morphology using microscopy (i) and by LDH release (j, l). The NT46 truncated protein is too small to be detected in k. Red arrows indicate ballooning pyroptotic cells. m, n, Effect of F2A mutation on GSDME-NT-induced pyroptosis in HEK293T cells. Protein expression is detected by anti-Flag immunoblot (m) and pyroptosis is assessed by LDH release (n). o, p, Effect of transient expression of mouse WT FL GSDME or wild-type or mutated GSDME-NT (mNT270, amino acids 1–270) in HEK293T cells (o) and on LDH release (p). q, r, Effect in 4T1E cells of expression of wild-type or mutated FL mGSDME (q) on raptinal-induced SYTOX green uptake (r). Differences among multiple groups in d, g, j, l, n, p, r were analysed by one-way ANOVA, using the Holm–Sidak method for multiple comparisons. Data are mean ± s.d. of three technical (d, g, j, l, n, p) or biological (r) replicates. P values compare unmutated with mutated constructs. ***P < 0.0001. Data are representative of three independent experiments.

Source data

Extended Data Fig. 4 Gsdme knockout in EMT6 and CT26 cells increases tumour growth and reduces immune responses within tumours.

aj, Comparison of control and Gsdme−/− orthotopic EMT6 tumours (control n = 6, Gsdme−/−n = 7) (ae) and subcutaneous CT26 tumours (control n = 6, Gsdme−/−n = 5) (fj) in BALB/c mice. The effects of knockout are demonstrated in Extended Data Fig. 1. Shown are tumour growth (a, f); numbers of CD8+ TILs (left), NK cells (middle) and tumour-associated macrophages (right), normalized to tumour weight (b); representative flow plots (left) and mean percentage of CD8+ TILs expressing GzmB or PFN (right) (c, g); mean percentages of NK cells expressing GzmB or PFN (d, h); and representative flow plots (left) and mean percentage of CD8TILs (right, e, i) and CD4+ TILs (j) producing IFNγ or TNF after PMA and ionomycin stimulation. The area under the curve in a, f and differences between two groups in be, gj were compared by two-tailed Student’s t-test. Data are mean + s.e.m. Data are representative of at least two independent experiments.

Source data

Extended Data Fig. 5 Effects of GSDME expression on tumour growth and immune responses within 4T1E tumours.

a, 4T1E cells stably expressing wild-type mGSDME (n = 6 mice per group), the inactive F2A mutant of mGSDME (n = 6 mice per group) or an empty vector (n = 7 mice per group), implanted in mammary fat pads, were analysed for tumour-infiltrating immune-cell numbers. be, 4T1E cells, stably expressing eGFP and then stably transduced to express mGSDME or empty vector (b), were compared for raptinal-induced SYTOX green uptake in vitro (c), tumour growth after orthotopic implantation (n = 7 mice per group) (d), and percentage of CD8+ TILs expressing GzmB or PFN (e). Comparisons in a were calculated by one-way ANOVA using the Holm–Sidak method for multiple comparisons; comparisons in e were calculated by two-tailed Student’s t-test; comparisons in c, d were calculated by comparing the difference between the areas under the curve by two-tailed Student’s t-test. Data shown are mean +  s.e.m. ***P < 0.0001. All data are representative of two independent experiments.

Source data

Extended Data Fig. 6 GSDME overexpression in B16 cells reduces tumour growth and increases immune responses within tumours.

a, Tumour growth in C57BL/6 mice that were implanted subcutaneously with B16 cells stably transduced with empty vector (n = 6 mice per group) or expressing mGSDME (n = 8 mice per group) or inactive F2A GSDME (n = 5 mice per group). b, Numbers of CD8+ (left) and NK (middle) TILs and tumour-associated macrophages (right) in tumours, normalized to tumour weight. c, Percentage of CD8+ TILs expressing GzmB or PFN (left), and IFNγ or TNF after PMA and ionomycin stimulation (right). d, Percentage of NK cells expressing GzmB or PFN. The area under the curve of tumour growth curves in a was compared by one-way ANOVA with Holm–Sidak correction for type I errors. Comparisons in bd were calculated by one-way ANOVA using the Holm–Sidak method for multiple comparisons. Data are mean +  s.e.m. All data are representative of at least two independent experiments.

Source data

Extended Data Fig. 7 Depletion of CD8+ T and NK cells in mice bearing EMT6 tumours.

ac, Experimental scheme (a) and representative flow plots of CD4+ and CD8+ T cells and NK cells in the peripheral blood (b) and tumours (c) of mice bearing EMT6 tumours treated with isotype control antibody or anti-CD8 and/or anti-asialo-GM1 antibodies in Fig. 2b. Samples were obtained on day 3 (blood) and day 11 (tumours) after tumour challenge. Data are representative of at least two independent experiments.

Extended Data Fig. 8 B16 tumour growth in mice depleted of CD8+ or NK cells.

a, Experimental scheme and growth of empty vector or mGSDME-positive B16 tumours in mice depleted of CD8+ T cells (n = 6 mice per group) or NK cells (n = 6 mice per group) or treated with an isotype control antibody. Empty vector, n = 6 mice per group; mGSDME-positive, n = 7 mice per group. b, c, Antibody depletion was verified by flow cytometry using peripheral blood mononuclear cells (PBMCs) on day 7 after tumour challenge or using TILs at the time of necropsy. Representative flow plots show depletion of CD8+ T cells (top) or NK cells (bottom) in the peripheral blood (b) and tumours (c) of mice bearing B16 empty vector or B16 GSDME tumours treated with isotype control, anti-CD8 or anti-NK1.1 antibodies. The area under the curve of tumour growth curves was compared by one-way ANOVA with Holm–Sidak correction for type I error. Data are mean + s.e.m. All data are representative of two independent experiments.

Source data

Extended Data Fig. 9 Necroptosis and ferroptosis are not involved in GSDME-mediated pyroptosis.

a, Effect of EGTA, necrostatin-1s (Nec-1s), α-tocopherol (Vit. E), ferrostatin-1 (Fer-1) and desferoxamine (DFO) on YT-cell-induced SYTOX green uptake in EV and hGSDME-positive HeLa cells. bg, Cell-death-related gene expression in mouse and human cancer cell lines. Ripk3 (b), RIPK3 (c), Mlkl (d), MLKL (e), Il1b (f) and IL1B (g) mRNA levels, relative to Gapdh or GAPDH, respectively, of the indicated mouse (b, d, f) or human (c, e, g) cancer cell lines were assayed by qRT–PCR. Data are mean ± s.d. of biological (a) or technical (bg) triplicates and are representative of two independent experiments.

Source data

Extended Data Fig. 10 PFN plus GzmB induce pyroptosis in SH-SY5Y cells.

ac, SH-SY5Y cells treated with PFN with or without GzmB or medium for 2 h were analysed by microscopy (a), immunoblot of cell lysates probed for GSDME and actin (c) or LDH release (b). In b, c, treatment was in the presence of 30 μM of caspase inhibitors as indicated. d, Effects of GSDME knockout on pyroptosis induced by PFN with or without GzmB, assessed after 1 h of treatment by LDH release. Differences among multiple groups in b, d were analysed by one-way ANOVA using the Holm–Sidak method for multiple comparisons. Data are mean ± s.d. of biological triplicate wells. ***P < 0.0001. Data are representative of two independent experiments.

Source data

Extended Data Fig. 11 Uncleavable D270A mutation blocks GSDME-mediated tumour protection and induction of anti-tumour immunity.

ad, B16 cells stably expressing empty vector (n = 7 mice per group), wild-type GSDME (n = 8 mice per group) or D270A uncleavable GSDME (n = 7 mice per group) were implanted in C57BL/6 mice and followed for tumour growth (a) and the functional phenotype of CD8+ and NK TILs (bd). Shown are the percentages of CD8+ or NK TILs expressing GzmB or PFN (b, c) and of CD8+ TILs expressing IFNγ or TNF induced by PMA and ionomycin (d). eh, 4T1E cells stably expressing empty vector, wild-type or D270A uncleavable GSDME were implanted in syngeneic (BALB/c, n = 6 mice per group) mice and followed for tumour growth (e) and the functional phenotype of CD8+ and NK TILs (fh). Shown are the percentages of CD8+ TILs expressing GzmB or PFN (f) or induced by PMA and ionomycin to express IFNγ or TNF (h) and of NK TILs expressing GzmB or PFN (g). i, j, Gsdme−/− EMT6 cells rescued by transduction with lentiviruses expressing empty vector, wild-type, F2A or D270A GSDME were examined by immunoblot for GSDME expression (i) and for tumour growth after orthotopic implantation in BALB/c mice (n = 8 mice per group) (j). Areas under the curve of tumour growth curves or differences among multiple groups were compared by one-way ANOVA with Holm–Sidak correction for type I error. Data are mean + s.e.m. All data are representative of two independent experiments.

Source data

Supplementary information

Supplementary Figure

This file contains Supplementary Figure 1: Uncropped blot scans.

Reporting Summary

Supplementary Video 1: Raptinal induces pyroptosis in B16 cells overexpressing Gsdme.

Cells were treated with 10 μM raptinal in the presence of 2.5 μM SYTOX green and were imaged by time-lapse confocal microscopy for 1 hr. Shown is the video of a representative field. Data are representative of three independent experiments. Scale bar, 20 μm.

Supplementary Video 2: Raptinal induces apoptosis in B16 cells transduced with empty vector.

Cells were treated with 10 μM raptinal in the presence of 2.5 μM SYTOX green were imaged by time-lapse confocal microscopy for 1 hr. Shown is the video of a representative field. Data are representative of three independent experiments. Scale bar, 20 μm.

Supplementary Video 3: Raptinal induces pyroptosis in HeLa cells overexpressing GSDME.

Cells were treated with 10 μM raptinal in the presence of 2.5 μM SYTOX green and were imaged by time-lapse confocal microscopy for 1 hr. Shown is the video of a representative field. Data are representative of two independent experiments. Scale bar, 20 μm.

Supplementary Video 4: Raptinal induces apoptosis in HeLa cells transduced with empty vector.

Cells were treated with 10 μM raptinal in the presence of 2.5 μM SYTOX green and were imaged by time-lapse confocal microscopy for 1 hr. Shown is the video of a representative field. Data are representative of two independent experiments with similar results. Scale bar, 20 μm.

Supplementary Video 5: YT NK cells induce pyroptosis in target HeLa cells overexpressing GSDME.

Vybrant DiD-labeled YT (magenta) cells were co-cultured with hGSDME+ HeLa in SYTOX green containing medium. 1 hour later, cells were imaged by time-lapse confocal microscopy for 90 min. Shown is the video of a representative field. Data are representative of three independent experiments. Scale bar, 10 μm.

Supplementary Video 6: YT NK cells induce apoptosis in target HeLa cells transduced with empty vector.

Vybrant DiD-labeled YT (magenta) cells were co-cultured with EV HeLa in SYTOX green containing medium. 1 hour later, cells were imaged by time-lapse confocal microscopy for 160 min. Shown is the video of a representative field. Data are representative of three independent experiments. Scale bar, 10 μm.

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Zhang, Z., Zhang, Y., Xia, S. et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature 579, 415–420 (2020). https://doi.org/10.1038/s41586-020-2071-9

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