Abstract

Desmoplastic melanoma is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, and is highly associated with ultraviolet light-induced DNA damage1. We analysed sixty patients with advanced desmoplastic melanoma who had been treated with antibodies to block programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1). Objective tumour responses were observed in forty-two of the sixty patients (70%; 95% confidence interval 57–81%), including nineteen patients (32%) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF1 mutations (fourteen out of seventeen cases) in these tumours. Immunohistochemistry analysis from nineteen desmoplastic melanomas and thirteen non-desmoplastic melanomas revealed a higher percentage of PD-L1-positive cells in the tumour parenchyma in desmoplastic melanomas (P = 0.04); these cells were highly associated with increased CD8 density and PD-L1 expression in the tumour invasive margin. Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.

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Acknowledgements

This study was funded in part by the Grimaldi Family Fund, the Parker Institute for Cancer Immunotherapy, National Institutes of Health (NIH) grants R35 CA197633 and P01 CA168585, the Ressler Family Fund, the Samuels Family Fund and the Garcia-Corsini Family Fund (to A.R.). Z.E. was supported in part by the Moffitt Cancer Center NCI Skin SPORE (5P50CA168536) and Moffitt’s Total Cancer Care Initiative and Collaborative Data Services (P30-CA076292) for this work. J.M.Z. is part of the UCLA Medical Scientist Training Program supported by NIH training grant GM08042. S.H.-L. was supported by a Young Investigator Award and a Career Development Award from the American Society of Clinical Oncology (ASCO), a Tower Cancer Research Foundation Grant, and a Dr. Charles Coltman Fellowship Award from the Hope Foundation. We acknowledge the Translational Pathology Core Laboratory (TPCL) and R. Guo, W. Li, J. Pang and M. H. Macabali from UCLA for blood and biopsy processing, and X. Li, L. Dong, J. Yoshizawa, and J. Zhou from the UCLA Clinical Microarray Core for sequencing expertise. G.V.L. is supported by an NHMRC Fellowship and The University of Sydney Medical Foundation. R.A.S. is supported by an NHMRC Fellowship.

Author information

Author notes

    • Jeffrey A. Sosman

    Present address: Northwestern University Medical Center, Chicago, Illinois, USA.

    • Zeynep Eroglu
    • , Jesse M. Zaretsky
    •  & Siwen Hu-Lieskovan

    These authors contributed equally to this work.

Affiliations

  1. University of California Los Angeles, Los Angeles, California, USA

    • Zeynep Eroglu
    • , Jesse M. Zaretsky
    • , Siwen Hu-Lieskovan
    • , Bartosz Chmielowski
    • , Xiaoyan Wang
    • , I. Peter Shintaku
    • , Cody Wei
    • , Alistair J. Cochran
    •  & Antoni Ribas
  2. Moffitt Cancer Center and University of South Florida, Tampa, Florida, USA

    • Zeynep Eroglu
    • , Dae Won Kim
    •  & Jane Messina
  3. The University of Texas-MD Anderson Cancer Center, Houston, Texas, USA

    • Dae Won Kim
    •  & Wen-Jen Hwu
  4. University of California San Francisco, San Francisco, California, USA

    • Alain Algazi
  5. Vanderbilt Ingram Cancer Center, Nashville, Tennessee, USA

    • Douglas B. Johnson
    •  & Jeffrey A. Sosman
  6. Melanoma Institute Australia, Sydney, New South Wales, Australia

    • Elizabeth Liniker
    • , Matteo S. Carlino
    • , Richard A. Scolyer
    •  & Georgina V. Long
  7. Westmead Hospital, Sydney, New South Wales, Australia

    • Ben Kong
    •  & Matteo S. Carlino
  8. Memorial Sloan Kettering Cancer Center, New York, New York, USA

    • Rodrigo Munhoz
    •  & Michael A. Postow
  9. Weill Cornell Medical College, New York, New York, USA

    • Rodrigo Munhoz
    •  & Michael A. Postow
  10. Georgetown Lombardi Cancer Center, Washington DC, USA

    • Suthee Rapisuwon
  11. Parker Institute for Cancer Immunotherapy, San Francisco, California, USA

    • Pier Federico Gherardini
  12. Mayo Clinic, Jacksonville, Florida, USA

    • Richard W. Joseph
  13. The University of Sydney, Sydney, New South Wales, Australia

    • Matteo S. Carlino
    • , Richard A. Scolyer
    •  & Georgina V. Long
  14. Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

    • Richard A. Scolyer
  15. Royal North Shore Hospital, Sydney, New South Wales, Australia

    • Georgina V. Long

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Contributions

Z.E., J.M.Z., S.H.-L. and A.R. developed the concepts. Z.E., S.H.-L, J.M.Z., and A.R. designed the experiments. Z.E., J.M.Z., S.H.-L. and A.R. interpreted the data. S.H.-L., I.P.S. and Z.E. performed IHC analyses. J.M.Z. performed genomic analyses. Z.E., A.R., B.C., D.W.K., A.A., D.B.J., E.L., B.K., R.M., S.R., J.A.S., R.J., M.A.P., M.S.C, W.-J.H., and G.V.L. clinically evaluated patients and contributed clinical data and tumour samples. R.A.S., J.M., and A.J.C. evaluated tumour samples. P.F.G. conducted the heat map analysis. X.W. performed statistical analyses. C.W. evaluated the non-DM clinical data. Z.E., J.M.Z., S.H.-L. and A.R. wrote the manuscript. S.H.-L. and A.R. supervised the project. All authors contributed to the manuscript and approved the final version.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Siwen Hu-Lieskovan or Antoni Ribas.

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https://doi.org/10.1038/nature25187

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