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High response rate to PD-1 blockade in desmoplastic melanomas

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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Figure 1: High response rate to PD-1 blockade in patients with DM.
Figure 2: High mutational load and similarity to NF1 subtype in DM.
Figure 3: CD8 density and PD-L1 expression in the tumour parenchyma and invasive margins from biopsies of patients with DM and non-DM tumours.

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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.

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Authors and Affiliations

Authors

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.

Corresponding authors

Correspondence to Siwen Hu-Lieskovan or Antoni Ribas.

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Extended data figures and tables

Extended Data Figure 1 Survival data for the DM cohort.

a, Progression-free survival (PFS), n = 60, median not reached. b, Overall survival (OS), n = 60, median not reached.

Extended Data Figure 2 Ultraviolet light-induced DNA damage signature in the desmoplastic melanoma cohort.

a, Cumulative percentage per DM sample (n = 17) of single nucleotide mutations by transition or transversion substitution. b, Mutation signature analysis9 on combined DM (n = 17) and non-DM (n = 23) cohorts14. All show the predominant C>T-rich signature characteristic of UV damage.

Extended Data Figure 3 Mutational analysis in the desmoplastic melanoma cohort.

a, Analysis of mutational load in samples obtained from primary locally advanced cases and metastatic lesions. Two-sided Wilcoxon Mann–Whitney rank sum test, P = 0.16 (95% CI, −171 to 1,175). b, Scores from the loss-of-function (LOF) SigRank algorithm1 show enrichment for LOF mutations (nonsense, frameshift, splice-site or damaging missense) compared to the expected number based on the rate of LOF mutations in the cohort. Solid line corresponds to observed/expected ratio of 1.0. c, Mutational load in the vanAllen16 anti-CTLA4 treated cohort separated by driver subtype and coloured by response. In the box plots, line is median, box is 25th to 75th percentile, whiskers show highest and lowest values within 1.5 × interquartile range.

Extended Data Figure 4 Mutations in antigen-presenting machinery or enriched by response in the DM cohort.

a, Mutations in genes enriched in responders (n = 12) (blue) or non-responders (n = 5) (red). Shown are genes with P < 0.05 by unadjusted two-sided Fisher’s exact test of samples with or without a non-synonymous mutation between responders and non-responders. None were significant after false-discovery rate adjustment. b, Mutations in antigen-presenting machinery genes. Tiling plot shows mutations in a given gene (rows) per sample (columns). Colour indicates mutation type, with truncating mutations (frameshift, nonsense, splice-site) in red, missense in green. Darker colour intensity indicates potentially homozygous mutations, with variant allele frequency more than 1.5 times the sample median.

Extended Data Figure 5 Patterns of CD8 infiltration and PD-L1 expression in biopsies from patients with DM and non-DM tumours.

ae, Using cut off of >10% for high CD8 density in either parenchyma or invasive margins and >15% for high PD-L1 expression, five different patterns were identified. a, High CD8 density, high PD-L1 in tumour parenchyma higher than in invasive margins. b, High CD8 density, high PD-L1 in invasive margins higher than in tumour parenchyma. c, High CD8 density, high PD-L1 in the invasive margins only. d, Low CD8 density, high PD-L1. e, Low CD8 density, low PD-L1 expression. f, Yellow lines delineate the edges of tumour regions determined by positive S100 staining. Green or red lines mark the invasive margins around the tumour edges. All analysis was done with HALO software (Indica Labs). g, Heat map summary of patterns of CD8 and PD-L1 expression in biopsies from patients with DM and CM, based on their response to anti-PD-1 or anti-PD-L1 treatment. Intensity of colour coding indicates number of cases in each category. All calculations were based on scanned whole tumour images.

Extended Data Figure 6 CD8 density and PD-L1 expression in the tumour parenchyma and invasive margins in biopsies of patients with DM and non-DM tumours.

a, CD8 staining in the invasive margin. b, PD-L1 staining in the invasive margin. c, CD8 staining in the tumour centre. d, PD-L1 staining in the tumour centre. The percentage of positively stained cells in all nucleated cells is shown. CB, clinical benefit; PD, progressive disease. All calculations used two-sided Mann–Whitney rank sum test. See Supplementary Table for all statistical analyses. Asterisk indicates statistical significance. Tumour, tumour centre.

Extended Data Figure 7 Correlation between CD8 and PD-L1 in the invasive margin or tumour parenchyma in DM.

Black squares represent a sample from a patient who had a good response in the lesion biopsied (analysed) but was found to have brain metastasis shortly after treatment started. See Supplementary Table for further statistical analyses. IM, invasive margin.

Extended Data Figure 8 Hierarchical clustering of cases of DM and non-DM based on CD8 and PD-L1 expression in the invasive margin and tumour parenchyma.

a, Non-desmoplastic cutaneous melanomas (n = 13), with the y axis colour coded for response and mutational load. b, Desmoplastic melanomas (n = 19), with the additional information of differentiation between pure (red) and mixed (blue) histology on the y axis. For mutational load, darker squares correspond to higher mutational load. Gray squares are missing data points.

Extended Data Table 1 Summary of patient characteristics
Extended Data Table 2 Summary of systemic drug treatments received by each patient

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Supplementary Information

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Eroglu, Z., Zaretsky, J., Hu-Lieskovan, S. et al. High response rate to PD-1 blockade in desmoplastic melanomas. Nature 553, 347–350 (2018). https://doi.org/10.1038/nature25187

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