Article

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

  • Nature Medicine volume 24, pages 165175 (2018)
  • doi:10.1038/nm.4463
  • Download Citation
Received:
Accepted:
Published:

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.

  • Subscribe to Nature Medicine for full access:

    $225

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

Accessions

Primary accessions

Gene Expression Omnibus

References

  1. 1.

    , & Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18, 884–901 (2010).

  2. 2.

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

  3. 3.

    & Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

  4. 4.

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

  5. 5.

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

  6. 6.

    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).

  7. 7.

    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).

  8. 8.

    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).

  9. 9.

    , & Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

  10. 10.

    , & Neutrophils in cancer: neutral no more. Nat. Rev. Cancer 16, 431–446 (2016).

  11. 11.

    , & Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

  12. 12.

    & The basis of oncoimmunology. Cell 164, 1233–1247 (2016).

  13. 13.

    , , & The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 37, 208–220 (2016).

  14. 14.

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

  15. 15.

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

  16. 16.

    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).

  17. 17.

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

  18. 18.

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

  19. 19.

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

  20. 20.

    , & The functions and regulation of the PTEN tumour suppressor. Nat. Rev. Mol. Cell Biol. 13, 283–296 (2012).

  21. 21.

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

  22. 22.

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

  23. 23.

    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).

  24. 24.

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

  25. 25.

    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).

  26. 26.

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

  27. 27.

    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).

  28. 28.

    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).

  29. 29.

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

  30. 30.

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

  31. 31.

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

  32. 32.

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

  33. 33.

    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).

  34. 34.

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

  35. 35.

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

  36. 36.

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

  37. 37.

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

  38. 38.

    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).

  39. 39.

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

  40. 40.

    , , , & Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice. J. Leukoc. Biol. 83, 64–70 (2008).

  41. 41.

    , , & Inhibition of tumor growth by elimination of granulocytes. J. Exp. Med. 181, 435–440 (1995).

  42. 42.

    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).

  43. 43.

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

  44. 44.

    & Review of S100A9 biology and its role in cancer. Biochim. Biophys. Acta 1835, 100–109 (2013).

  45. 45.

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

  46. 46.

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

  47. 47.

    , , & Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J. Clin. Invest. 125, 3365–3376 (2015).

  48. 48.

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

  49. 49.

    , & Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).

  50. 50.

    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).

  51. 51.

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

  52. 52.

    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).

  53. 53.

    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).

  54. 54.

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

  55. 55.

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

  56. 56.

    , & A review of tasquinimod in the treatment of advanced prostate cancer. Drug Des. Devel. Ther. 7, 167–174 (2013).

  57. 57.

    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).

  58. 58.

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

  59. 59.

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

  60. 60.

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

  61. 61.

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

  62. 62.

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

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

Author notes

    • Marco Bezzi
    • , Nina Seitzer
    •  & Tomoki Ishikawa

    These authors contributed equally to this work.

Affiliations

  1. Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

    • Marco Bezzi
    • , Nina Seitzer
    • , Tomoki Ishikawa
    • , Markus Reschke
    • , Ming Chen
    • , Guocan Wang
    • , Caitlin Mitchell
    • , Christopher Ng
    • , Jesse Katon
    • , Andrea Lunardi
    • , John G Clohessy
    •  & Pier Paolo Pandolfi
  2. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Sabina Signoretti
  3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Sabina Signoretti
  4. Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

    • John G Clohessy
  5. School of Biological Sciences, University of Hong Kong, Hong Kong SAR, China.

    • Jiangwen Zhang

Authors

  1. Search for Marco Bezzi in:

  2. Search for Nina Seitzer in:

  3. Search for Tomoki Ishikawa in:

  4. Search for Markus Reschke in:

  5. Search for Ming Chen in:

  6. Search for Guocan Wang in:

  7. Search for Caitlin Mitchell in:

  8. Search for Christopher Ng in:

  9. Search for Jesse Katon in:

  10. Search for Andrea Lunardi in:

  11. Search for Sabina Signoretti in:

  12. Search for John G Clohessy in:

  13. Search for Jiangwen Zhang in:

  14. Search for Pier Paolo Pandolfi in:

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Pier Paolo Pandolfi.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–10 and Supplementary Tables 1–5

  2. 2.

    Life Sciences Reporting Summary