Abstract
Aberrant activation of oncogenes or loss of tumour suppressor genes opposes malignant transformation by triggering a stable arrest in cell growth, which is termed cellular senescence1,2,3. This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence4,5,6. Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours in mice2,7 are massively infiltrated by a population of CD11b+Gr-1+ myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-1+ cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype of the tumour through the secretion of interleukin-1 receptor antagonist (IL-1RA). Strikingly, Pten-loss-induced cellular senescence was enhanced in vivo when Il1ra knockout myeloid cells were adoptively transferred to PTEN null mice. Therapeutically, docetaxel-induced senescence and efficacy were higher in PTEN null tumours when the percentage of tumour-infiltrating CD11b+Gr-1+ myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2)8. Taken together, our findings identify a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy.
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Change history
05 November 2014
A minor change was made to the author list.
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Acknowledgements
We thank L. Bühler for providing the Il1ra knockout mice, the F. Grassi laboratory and all members of the IRB animal core facility for technical assistance and the animal work, F. Stoffel for providing human samples, D. Jarrossay for helping with the flow cytometry analysis and cell sorting experiments, and all members of the Alimonti laboratory for scientific discussions. We thank C. Pissot-Soldermann, who developed NVP-BSK805. We thank T. Radimersky for providing NVP-BSK805. The human tissue microarray (as described in ref. 26) was obtained from the Department of Defense Prostate Cancer Research Program, Awards W81XWH-10-2-0056 and W81XWH-10-2-0046, Prostate Cancer Biorepository Network (PCBN). We thank G. Chiorino, I. Gregnanin, P. Ostano and L. Sacchetto for the gene expression analysis performed on myeloid and tumour cells. This work was supported by Swiss national science foundation (SNF) grant Ambizione (PZ00P3_136612/1), the European Society for Medical Oncology (ESMO) translational research award to A.A., the Swiss Bridge Award to A.A., PEOPLE-IRG (22484), a European Research Council starting grant (ERCsg 261342), ABREOC, the Train COFUND Marie Curie to D.D.M. and Fondazione IBSA.
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Authors and Affiliations
Contributions
A.A. and A.T. originally developed the concept, further elaborated on it and designed the experiments together with D.D.M. D.D.M., A.T. and J.J.C. performed experiments and analysed the data. R.D., E.M., A.T. and D.D.M. established and carried out fluorescence microscopy. D.D.M. and T.R.J. carried out adoptive transfer experiments. M.S. and S.P. performed immunohistochemical experiments and analysis. I.G. performed experiments, R.G.-E. and C.C. carried out the bioinformatics analysis. S.D.S.-A. and M.C. provided the K-ras+/G12V tumour samples. M.E. and Z.Z. provided tumour samples for the human prostate cancer study. A.T., D.D.M., F.G. and A.A. interpreted the data and wrote the paper. D.D.M. and A.T. contributed equally to this work.
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Extended data figures and tables
Extended Data Figure 1 Gr-1+ myeloid cells infiltrate senescent tumours in Ptenpc−/− mice.
a, Representative SA-β-gal staining of prostate sections from 8-week-old Ptenpc+/+ and Ptenpc−/− mice. Original magnification, ×400. b, Representative confocal immunofluorescence (IF) images showing staining of the epithelial marker cytokeratin 18 (CK18) (grey) and the senescence marker pHP1γ (green) in prostate tumours from Ptenpc−/− mice. Cells were counterstained with the nuclear marker DAPI (blue). A Ptenpc+/+ prostate negative for pHP1γ staining is also shown (inset). c, Representative confocal IF image showing proliferating epithelial cells (CK18, grey; Ki-67, red) and senescent epithelial cells (cytokeratin 18, grey; pHP1γ, green) in Ptenpc−/− prostate lesions. Cells were counterstained with the nuclear marker DAPI (blue). The histogram shows the quantification of CK18+pHP1γ+Ki-67−, CK18+pHP1γ−Ki-67+ and CK18+pHP1γ+Ki-67+ cells (n = 3; 1 tumour per mouse; 10 fields acquired; 412 cells counted). d, Quantification of CD11b+Gr-1+ immune cells in 8-week-old Ptenpc+/+ and Ptenpc−/− mice (n = 6). e, Flow cytometry analysis showing the heterogeneity of the tumour-infiltrating CD45+CD11b+Gr-1+ immune cells in Ptenpc−/− prostates. f, In Ptenpc−/− tumours, the senescence response starts at 8 weeks of age (top). A time course experiment is shown, indicating the recruitment of Gr-1+ myeloid cells in Ptenpc+/− and Ptenpc−/− mice at the onset of tumorigenesis (bottom) (n = 3 per group; 1 tumour per mouse). g, Correlation between Ki-67 staining and percentage of Gr-1+ myeloid cells in the anterior (AP) and dorsolateral lobes (DLP) of Ptenpc−/− tumours (n = 3; 1 tumour per mouse). h, Experimental scheme. Ptenpc−/− mice were lethally irradiated and then transferred with bone marrow from UBC-GFP mice that had been depleted of T-, B- and natural killer (NK) cells. Prostate tissues were collected 4 weeks after transfer. i, Representative confocal IF images showing the localization of myeloid cells (green) infiltrating the anterior prostate gland of Ptenpc−/−UBC-GFP mice. Proliferating cells (Ki-67, red) and stroma (vimentin, grey) are also shown. Cells were counterstained with DAPI (blue). j, Representative confocal IF image showing the localization of tumour-infiltrating UBC-GFP cells and proliferating epithelial cells (CK18, grey; Ki-67, red) in prostate lesions from Ptenpc−/−UBC-GFP mice. Cells were counterstained with the nuclear marker DAPI (blue). Arrows indicate CK18+Ki-67+ cells, which were considered for the analysis, while * indicates CK18−Ki-67+ cells, which were excluded from the analysis. k, Quantification of UBC-GFP+Gr-1+ cells (n = 4; 1 tumour per mouse; 5 fields acquired; 300 cells counted). l, Representative confocal IF image showing the localization of tumour-infiltrating myeloid cells (Gr-1, red) and proliferating epithelial cells (CK18, grey; Ki-67, green) in prostate lesions from non-irradiated Ptenpc−/− mice. Cells were counterstained with the nuclear marker DAPI (blue). The histogram shows the quantification of the distance between tumour-infiltrating Gr-1+CK18− myeloid cells and CK18+Ki-67+ proliferating epithelial cells (n = 3; 10 fields acquired; 334 measurements). The arrows indicate CK18+Ki-67+ cells, which were considered for the analysis. m, Experimental set-up. n, Flow cytometry and qRT–PCR analysis of Gr-1+ myeloid cells differentiated in vitro in the presence of granulocyte–macrophage colony-stimulating factor (GM-CSF) and IL-6, showing upregulation of Gr-1 and Il10 mRNA. o, SA-β-gal staining of Pten−/− MEFs. c, d, f, g, k, l, n, Error bars, mean ± s.e.m. P values were derived from an unpaired, two-tailed Student’s t-test (**P < 0.01; ***P < 0.001).
Extended Data Figure 2 Gene expression analysis of factors expressed by Gr-1+ myeloid cells and epithelial cells sorted from Ptenpc−/− tumours.
a, Experimental set-up (top). Protein levels of IL-1RA in Ptenpc−/− bulk prostate tumours and Ptenpc−/− immunodepleted prostatic epithelial cells (bottom) (n = 3 per group; 1 tumour per mouse). b, Experimental set-up. Gene expression analysis of epithelial cells and Gr-1+ myeloid cells purified from Ptenpc−/− prostate tumours. Briefly, prostates were isolated from 8-week-old Ptenpc−/− mice and processed to a single-cell suspension. CD45− epithelial cells and CD45+CD11b+Gr-1+ myeloid cells were further sorted using a FACSAria Cell Sorter. Total RNA was isolated from the epithelial and myeloid cell populations, and gene expression profiling was carried out using the one-colour labelling method, performing two replicates for each condition. A heatmap displaying the mRNA expression of 53 secreted factors is shown (n = 2 per group). c, qRT–PCR analysis of CD11b+Gr-1−F4/80+ sorted from Ptenpc−/− prostate tumours, showing Il1ra expression (n = 3). a, c, Error bars, mean ± s.e.m. P values were derived from an unpaired, two-tailed Student’s t-test (**P < 0.01; ***P < 0.001).
Extended Data Figure 3 Gr-1+ myeloid cells oppose senescence in both Pten-loss-induced cellular senescence and oncogene-induced senescence.
a, Western blot analysis showing the inverse correlation between IL-1RA and p16INK4A protein levels in the anterior (AP) and dorsolateral lobes (DLP) of Ptenpc−/− prostate tumours. Levels are normalized to E-cadherin expression. b, Il1ra mRNA expression of bone marrow precursors (BMPs) and Gr-1+ myeloid cells sorted from Ptenpc−/− prostate tumours (n = 3). c, Cell growth of H-ras MEFs cultured in the presence of conditioned medium from Gr-1+ myeloid cells (n = 3). d, Quantification (left) and representative images (right) of SA-β-gal+ H-ras MEFs cultured in the presence of conditioned medium from Gr-1+ myeloid cells (n = 3). e, Il1ra mRNA expression of Gr-1+ myeloid cells differentiated for 4 days with IL-6 and GM-CSF, in the absence or presence of the JAK2 inhibitor NVP-BSK805, compared with bone marrow precursors (BMPs) (n = 3). f, Quantification (left) and representative images (right) of SA-β-gal+ Pten−/− MEFs cultured in the presence of conditioned medium from Gr-1+ myeloid cells that had been pre-treated with the JAK2 inhibitor NVP-BSK805 (n = 3). a–f, Error bars, mean ± s.e.m. P values were derived from an unpaired, two-tailed Student’s t-test (**P < 0.01; ***P < 0.001).
Extended Data Figure 4 IL-1RA opposes docetaxel-induced senescence in LNCaP cancer cells in vitro.
a, Histogram showing the quantification of pHP1γ+ cells. Briefly, LNCaP prostate cancer cells were cultured in the absence or presence of docetaxel, with or without human recombinant IL-1RA. After 5 days, cells were collected and stained for immunofluorescence analysis. Representative confocal IF staining showing senescent pHP1γ+ (red) LNCaP cancer cells (inset). Cells were counterstained with the nuclear marker DAPI (blue). b, Cell growth of LNCaP cells cultured in the absence or presence of docetaxel, with or without human recombinant IL-1RA (n = 3). a, b, Error bars, mean ± s.e.m. P values were derived from an unpaired, two-tailed Student’s t-test (*P < 0.01; ***P < 0.001).
Extended Data Figure 5 Gr-1+ myeloid cells infiltrate adenocarcinoma areas in lungs from K-ras+/G12V mice.
a, Haematoxylin and eosin (H&E), p16INK4A, p19ARF, Gr-1, IL-1RA and Ki-67 immunohistochemical staining in lungs from K-ras+/G12V mice. Original magnification, ×400. Staining of both adenocarcinoma and adenoma areas is shown (left). Histograms showing quantification of cells positive for p16INK4A, p19ARF, Gr-1, IL-1RA and Ki-67 (right) (n = 7; 3 sections per mouse; ≥5 fields per section analysed). b, c, Representative confocal IF images showing staining of Ki-67 (green) and the myeloid marker Gr-1 (red) with (b) or without (c) the epithelial marker CK18 (grey), in adenocarcinoma and adenoma areas of lungs from K-rasG12V mice. Cells were counterstained with the nuclear marker DAPI (blue). Panel b magnification × 400. Panel c magnification × 200. Top panel insets in c show H&E staining (magnification ×100) of the same areas stained for IF; bottom panels, magnification × 400. a, Error bars, mean ± s.e.m. P values were derived from an unpaired, two-tailed Student’s t-test (*P < 0.05; **P < 0.01; ***P < 0.001).
Extended Data Figure 6 Senescence and apoptotic markers in Ptenpc+/+Il1ra+/+ and Ptenpc−/−Il1ra−/− mice.
a, mRNA levels of Il1ra in BMPs from the indicated genotypes (n = 3). b, Quantification of Ki-67 staining. c, d, p16INK4A mRNA and protein levels. e, PAI1 mRNA and protein levels. f, SA-β-gal staining in prostate tissues from Ptenpc+/+Il1ra+/+ and Ptenpc−/−Il1ra−/− mice (n = 4 mice per group; 1 tumour per mouse; 3 sections per tumour; ≥5 fields per section). g, Ki-67 and p16INK4A immunohistochemical staining of stage-matched prostate tumours from Ptenpc+/+Il1ra+/+ and Ptenpc−/−Il1ra−/− mice. The histograms show quantification of Ki-67 and p16INK4A positivity (n = 4 mice per group; 1 tumour per mouse; 3 sections per tumour; 3 fields per section). h, Immunohistochemistry for cleaved caspase-3 in prostate tissues from Ptenpc+/+Il1ra+/+ and Ptenpc−/−Il1ra−/− mice. a–e, g, h, Error bars, mean ± s.e.m. P values were derived from an unpaired, two-tailed Student’s t-test (*P < 0.05; **P < 0.01; ***P < 0.001).
Extended Data Figure 7 Efficiency of magnetic-activated cell sorting (MACS) purification and bone marrow transplantation.
a, Representative flow cytometry plots showing whole bone marrow cells, phycoerythrin (PE)-positive cells isolated after magnetic separation and bone marrow cells depleted of T, NK and B cells before adoptive transfer to irradiated Ptenpc−/− mice (gating on total cells). Briefly, cells were flushed from the long bones of donor mice and stained with the following anti-mouse antibodies: anti-CD3–PE, anti-NK1.1–PE and anti-CD19–PE. The cells were then washed and stained with anti-PE magnetic beads and collected for magnetic separation. b, Representative plots obtained from flow cytometry analysis of splenocytes isolated from Ptenpc−/− mice before and after lethal irradiation (top). Immune reconstitution 14 days after bone marrow transplantation (bottom).
Extended Data Figure 8 Effect of IL1-α and CXCR2a on Ptenpc−/− tumours.
a, Experimental scheme. Briefly, osmotic pumps were implanted in the peritoneal cavity of six Ptenpc−/− mice, to expose the prostate tissue to a continuous and controlled concentration of either IL-1α or PBS. b, Immunohistochemical staining (H&E, Ki-67 and p16INK4A) of prostate sections from Ptenpc−/− mice treated with IL-1α or PBS. c–e, Histograms showing quantification of glands affected by prostatic intraepithelial neoplasia (PIN) (c), Ki-67 positivity (d) and p16INK4A positivity (e) (n = 3 per group; 1 tumour per mouse; 3 sections per mouse; 3 fields per sections were analysed). f, Protein profile of immunodepleted epithelial cells showing the high levels of cytokines that recruit (CXCL1 and CXCL2) and activate (GM-CSF and IL-6) Gr-1+ myeloid cells in Ptenpc−/− prostate tumours. g, Experimental set-up. Doce, docetaxel. h, Flow cytometry plots showing the reduced recruitment of Gr-1+ myeloid cells in Ptenpc−/− mice after treatment with a CXCR2 antagonist (CXCR2a), with gating on live CD45+ cells. The histogram shows the frequency of Gr-1+ myeloid cells (n = 5 control group; n = 7 treated groups). i, j, Flow cytometry plots showing the recruitment of Gr-1+ myeloid cells to the peripheral lymph nodes (upper panels) and spleen (lower panel) isolated from Ptenpc−/− mice, after treatment with CXCR2a, with gating on live cells. The histograms (right) show the frequency of Gr-1+ myeloid cells in the lymph nodes and spleen from Ptenpc−/− mice, after treatment with CXCR2a (n = 5 mice per group). c–f, h–j, Error bars, mean ± s.e.m. P values were derived from an unpaired, two-tailed Student’s t-test (*P < 0.05; **P < 0.01; ***P < 0.001).
Extended Data Figure 9 Treatment with a CXCR2 antagonist in vivo.
a, Il1ra mRNA levels in Ptenpc−/− tumours after treatment with CXCR2a alone or in combination with docetaxel. b, Immunohistochemical staining (H&E and SA-β-gal) in mice treated with CXCR2a and docetaxel. c, Quantification of cleaved caspase-3 in Ptenpc−/− tumours after the indicated treatments. d, Immunohistochemical staining for Ki-67 in stage-matched prostate tumours from Ptenpc−/− mice after treatment. The histograms show quantification of Ki-67 and p16INK4A positivity. e, f, Treatment of Pten−/− MEFs with CXCR2a (n = 3). NS, not significant. g, Staining and quantification of IL-1RA in primary tumours from patients. Responder patients (“R”) and non-responder patients (“NR”), based on disease-free survival. a, c–e, Error bars, mean ± s.e.m. P values were derived from an unpaired, two-tailed Student’s t-test (*P < 0.05; **P < 0.01). b–d, Control n = 5; treated n = 7; 3 sections per mouse; 5 fields per section.
Extended Data Figure 10 Evidence in human samples and proposed model.
a, b, Graphs showing the inverse association between p16INK4A and CD33 in the tissue microarrays and single prostate sections from human prostate cancer. Box plots in a show the interquartile range, whiskers show the full range. c, Histogram showing the percentage of cases positive for Ki-67, p16INK4A and CD33 in sections. Normal-like prostate areas were compared with PIN and prostate cancer (PCA) areas in the same section. d, Kaplan–Meier analysis (see the Survival curves subsection in Methods). e, Gr-1+ myeloid cells recruited to the tumour site oppose Pten-loss-induced cellular senescence by secreting IL-1RA in the tumour microenvironment. f, Gr-1+ myeloid cells can protect tumour cells from senescence by tilting the balance between IL-1α and IL-1RA in the tumour microenvironment. Pharmacological interventions aimed at impairing Gr-1+ myeloid cell recruitment (for example, CXCR2a) can enhance senescence, thus improving chemotherapy efficacy. CIS, chemotherapy induced senescence. a, Correlation assessed with Fisher’s exact test.
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Di Mitri, D., Toso, A., Chen, J. et al. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature 515, 134–137 (2014). https://doi.org/10.1038/nature13638
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DOI: https://doi.org/10.1038/nature13638
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