Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Diverse genetic-driven immune landscapes dictate tumor progression through distinct mechanisms

Abstract

Multiple immune-cell types can infiltrate tumors and promote progression and metastasis through different mechanisms, including immunosuppression. How distinct genetic alterations in tumors affect the composition of the immune landscape is currently unclear. Here, we characterized the immune-cell composition of prostate cancers driven by the loss of the critical tumor suppressor gene Pten, either alone or in combination with the loss of Trp53, Zbtb7a or Pml. We observed a striking quantitative and qualitative heterogeneity that was directly dependent on the specific genetic events in the tumor and ranged from 'cold', noninflamed tumors to massively infiltrated landscapes—results with important therapeutic implications. Further, we showed these qualitative differences in transcriptomic analysis of human prostate cancer samples. These data suggest that patient stratification on the basis of integrated genotypic–immunophenotypic analyses may be necessary for successful clinical trials and tailored precision immunological therapies.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The genetic makeup of prostate cancer dictates the composition of immune infiltrates in primary tumors.
Figure 2: Characterization of Gr-1+CD11b+ cells in Ptenpc−/−; Zbtb7apc−/− and Ptenpc−/−; Trp53pc−/− prostate tumors.
Figure 3: Differential mechanisms of Gr-1+CD11b+ cell recruitment in Ptenpc−/−; Zbtb7apc−/− and Ptenpc−/−; Trp53pc−/− tumors.
Figure 4: CXCL5 and CXCL17 are chemoattractants for PMN cells and monocytes, respectively.
Figure 5: Gr-1+CD11b+ cells in Ptenpc−/−; Zbtb7apc−/− and Ptenpc−/−; Trp53pc−/− prostate tumors promote tumor growth.
Figure 6: Clinical relevance of the genotype–chemokine–immunophenotype axis of prostate tumor models.

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. 1

    Egeblad, M., Nakasone, E.S. & Werb, Z. Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18, 884–901 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Hanahan, D. & Coussens, L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).

    Article  CAS  Google Scholar 

  3. 3

    Quail, D.F. & Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Nakasone, E.S. et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 21, 488–503 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Zou, W., Wolchok, J.D. & Chen, L. PD-L1 (B7–H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci. Transl. Med. 8, 328rv4 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Small, E.J. et al. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin. Cancer Res. 13, 1810–1815 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. 7

    Slovin, S.F. et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann. Oncol. 24, 1813–1821 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Kwon, E.D. et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 15, 700–712 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Gabrilovich, D.I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Coffelt, S.B., Wellenstein, M.D. & de Visser, K.E. Neutrophils in cancer: neutral no more. Nat. Rev. Cancer 16, 431–446 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. 11

    Grivennikov, S.I., Greten, F.R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Palucka, A.K. & Coussens, L.M. The basis of oncoimmunology. Cell 164, 1233–1247 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Kumar, V., Patel, S., Tcyganov, E. & Gabrilovich, D.I. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 37, 208–220 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Chen, D.S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017).

    Article  CAS  PubMed  Google Scholar 

  15. 15

    Trotman, L.C. et al. Pten dose dictates cancer progression in the prostate. PLoS Biol. 1, E59 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Wang, G. et al. Zbtb7a suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion. Nat. Genet. 45, 739–746 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Chen, M. et al. An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer. Nat. Genet. in press (2018).

  19. 19

    Lunardi, A. et al. A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer. Nat. Genet. 45, 747–755 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Song, M.S., Salmena, L. & Pandolfi, P.P. The functions and regulation of the PTEN tumour suppressor. Nat. Rev. Mol. Cell Biol. 13, 283–296 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. 21

    Di Mitri, D. et al. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature 515, 134–137 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. 22

    Bronte, V. et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7, 12150 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Garcia, A.J. et al. Pten null prostate epithelium promotes localized myeloid-derived suppressor cell expansion and immune suppression during tumor initiation and progression. Mol. Cell. Biol. 34, 2017–2028 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Acharyya, S. et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165–178 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Bruchard, M. et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat. Med. 19, 57–64 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. 26

    Bald, T. et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507, 109–113 (2014).

    Article  CAS  PubMed  Google Scholar 

  27. 27

    Huang, B. et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res. 66, 1123–1131 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. 28

    Pan, P.-Y. et al. Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res. 70, 99–108 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. 29

    Kowanetz, M. et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc. Natl. Acad. Sci. USA 107, 21248–21255 (2010).

    Article  PubMed  Google Scholar 

  30. 30

    Corzo, C.A. et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med. 207, 2439–2453 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Franklin, R.A. et al. The cellular and molecular origin of tumor-associated macrophages. Science 344, 921–925 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Movahedi, K. et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 70, 5728–5739 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. 33

    Walz, A. et al. Structure and neutrophil-activating properties of a novel inflammatory peptide (ENA-78) with homology to interleukin 8. J. Exp. Med. 174, 1355–1362 (1991).

    Article  CAS  PubMed  Google Scholar 

  34. 34

    Koch, A.E. et al. Epithelial neutrophil activating peptide-78: a novel chemotactic cytokine for neutrophils in arthritis. J. Clin. Invest. 94, 1012–1018 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Wang, G. et al. Targeting YAP-dependent MDSC infiltration impairs tumor progression. Cancer Discov. 6, 80–95 (2016).

    Article  CAS  PubMed  Google Scholar 

  36. 36

    Kukita, A. et al. Osteoclast-derived zinc finger (OCZF) protein with POZ domain, a possible transcriptional repressor, is involved in osteoclastogenesis. Blood 94, 1987–1997 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. 37

    Maeda, T. et al. Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature 433, 278–285 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. 38

    Pisabarro, M.T. et al. Cutting edge: novel human dendritic cell- and monocyte-attracting chemokine-like protein identified by fold recognition methods. J. Immunol. 176, 2069–2073 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. 39

    Marigo, I. et al. Tumor-induced tolerance and immune suppression depend on the C/EBPβ transcription factor. Immunity 32, 790–802 (2010).

    Article  CAS  Google Scholar 

  40. 40

    Daley, J.M., Thomay, A.A., Connolly, M.D., Reichner, J.S. & Albina, J.E. Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice. J. Leukoc. Biol. 83, 64–70 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. 41

    Pekarek, L.A., Starr, B.A., Toledano, A.Y. & Schreiber, H. Inhibition of tumor growth by elimination of granulocytes. J. Exp. Med. 181, 435–440 (1995).

    Article  CAS  PubMed  Google Scholar 

  42. 42

    White, J.R. et al. Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration. J. Biol. Chem. 273, 10095–10098 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. 43

    Stadtmann, A. & Zarbock, A. CXCR2: from bench to bedside. Front. Immunol. 3, 263 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Markowitz, J. & Carson, W.E., III. Review of S100A9 biology and its role in cancer. Biochim. Biophys. Acta 1835, 100–109 (2013).

    CAS  PubMed  Google Scholar 

  45. 45

    Stylianou, E. & Saklatvala, J. Interleukin-1. Int. J. Biochem. Cell Biol. 30, 1075–1079 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. 46

    Gentles, A.J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Ugel, S., De Sanctis, F., Mandruzzato, S. & Bronte, V. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J. Clin. Invest. 125, 3365–3376 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215–1228 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Spranger, S., Bao, R. & Gajewski, T.F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. 50

    Seliger, B. et al. Down-regulation of the MHC class I antigen-processing machinery after oncogenic transformation of murine fibroblasts. Eur. J. Immunol. 28, 122–133 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. 51

    Atkins, D. et al. MHC class I antigen processing pathway defects, ras mutations and disease stage in colorectal carcinoma. Int. J. Cancer 109, 265–273 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. 52

    Bradley, S.D. et al. BRAFV600E co-opts a conserved MHC class I internalization pathway to diminish antigen presentation and CD8+ T-cell recognition of melanoma. Cancer Immunol. Res. 3, 602–609 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Borrello, M.G. et al. Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene. Proc. Natl. Acad. Sci. USA 102, 14825–14830 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. 54

    Matsui, A. et al. CXCL17 expression by tumor cells recruits CD11b+Gr1high F4/80- cells and promotes tumor progression. PLoS One 7, e44080 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Lunardi, A. et al. A role for PML in innate immunity. Genes Cancer 2, 10–19 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Williamson, S.C., Hartley, A.E. & Heer, R. A review of tasquinimod in the treatment of advanced prostate cancer. Drug Des. Devel. Ther. 7, 167–174 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Pili, R. et al. Phase II randomized, double-blind, placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer. J. Clin. Oncol. 29, 4022–4028 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. 58

    Patnaik, A. et al. Cabozantinib eradicates advanced murine prostate cancer by activating antitumor innate immunity. Cancer Discov. 7, 750–765 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Lu, X. et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature 543, 728–732 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Drost, J. et al. Organoid culture systems for prostate epithelial and cancer tissue. Nat. Protoc. 11, 347–358 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the members of the laboratory of P.P.P. for critically reading and discussing the manuscript. We thank N. Pandell of the Preclinical Murine Pharmacogenetics Core at BIDMC, K. Berry and the members of the Center of Life Science animal facility for helping with all in vivo work. We thank the members of the Dana Farber Flow Cytometry Facility and the BIDMC Flow Cytometry Core for the help with all cell sorting. We also thank the Small Animal Imaging Core at BIDMC for the magnetic resonance imaging (MRI) work. This work was funded by NIH grants R01 CA102142 and R35 CA197529 awarded to P.P.P. and was supported by a Jane Coffin Childs Postdoctoral Fellowship to M.B.

Author information

Affiliations

Authors

Contributions

M.B., N.S., T.I., M.R., A.L. and P.P.P. designed the study; M.B., N.S., T.I. and M.R. developed methodology; M.B., N.S., T.I., M.R. and G.W. performed experiments; G.W., C.M., C.N., M.C., A.L., S.S. and J.G.C. provided administrative, technical or material support; N.S., T.I., C.N., J.K., A.L. and S.S. performed histology and immunohistochemistry; J.Z. performed bioinformatics analysis; M.B., N.S., T.I., M.R. and P.P.P. analyzed and interpreted data; M.B., N.S., T.I., M.R. and P.P.P. wrote the manuscript; P.P.P. supervised the study.

Corresponding author

Correspondence to Pier Paolo Pandolfi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 and Supplementary Tables 1–5 (PDF 7146 kb)

Life Sciences Reporting Summary (PDF 327 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bezzi, M., Seitzer, N., Ishikawa, T. et al. Diverse genetic-driven immune landscapes dictate tumor progression through distinct mechanisms. Nat Med 24, 165–175 (2018). https://doi.org/10.1038/nm.4463

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing