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TNFSF4 (OX40L) expression and survival in locally advanced and metastatic melanoma

  • Jason Roszik
  • Ettai Markovits
  • Paula Dobosz
  • Adi Layani
  • Keren Slabodnik-Kaner
  • Erez N. Baruch
  • Guy Ben-Betzalel
  • Elizabeth Grimm
  • Raanan Berger
  • Yehezkel Sidi
  • Jacob Schachter
  • Ronnie Shapira-Frommer
  • Dror Avni
  • Gal MarkelEmail author
  • Raya Leibowitz-AmitEmail author
Original Article

Abstract

Immunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), and RNA sequencing data from anti-PD1-treated patients at Sheba medical center. TNFSF4 mRNA is expressed in melanoma cell lines and melanoma samples, including those with low lymphocytic infiltrates, and is not associated with the ulceration status of the primary tumor. Low expression of TNFSF4 mRNA is associated with worse prognosis in all melanoma patients and in the cohorts of stage III and stage IIIc–IV patients. Low expression of TNFSF4 mRNAs is also associated with worse prognosis in the subgroup of patients with low lymphocytic infiltrates, suggesting that tumoral TNFSF4 is associated with outcome. TNFSF4 expression was not correlated with the expression of other known checkpoint mRNAs. Last, metastatic patients with TNFSF4 mRNA expression within the lowest quartile have significantly worse outcome on anti-PD1 treatment, and a significantly lower response rate to these agents. Our current work points to TNFSF4 expression in melanoma as a potential determinant of prognosis, and warrants further translational and clinical research.

Keywords

Melanoma Immunotherapy Immune-oncology TNFSF4 Survival OX40L 

Abbreviations

CAF

Cancer-associated fibroblasts

CCLE

Cancer Cell Line Encyclopedia

LS

Lymphocyte score

OS

Overall survival

PFS

Progression-free survival

RPKM

Reads per kilo-base per million

TCGA

The Cancer Genome Atlas

TIL

Tumor infiltrating lymphocytes

TPM

Transcripts per million

Notes

Author contributions

JR, EM, GM, and RL-A: conceived and designed the analysis; ENB, GB–B, JS and RS-F: collected the data; JR, EM, PD, AL, KS-K, EG, RB, YS, DA, GM and RL-A: performed the analysis; JR and RL-A: wrote the paper. All authors read, commented and approved the paper.

Funding

This work was partly funded by a grant from the Sister-Institution-Network-Fund (SINF) of the M.D. Anderson Cancer Center (MDACC) and the Sheba medical center, and by a research grant from the Israeli Scientific Foundation (ISF) # 16/1419. G.M. is supported by the Lemelbaum family fund and the Samueli Foundation Grant for integrative immuno-oncology.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no relevant conflicts of interest.

Ethical approval and ethical standards

We analyzed the publicly available TCGA and CCLE databases. Use of these data does not mandate patient informed consent. The retrospective data analysis of patient samples was approved by the institutional review board of the Sheba medical center, Tel Hashomer, Israel (Approval # SMC-2411/15).

Informed consent

All patients signed an informed consent allowing the analysis and publication of anonymized data.

Supplementary material

262_2019_2382_MOESM1_ESM.pdf (616 kb)
Supplementary material 1 (PDF 615 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jason Roszik
    • 1
  • Ettai Markovits
    • 2
    • 3
  • Paula Dobosz
    • 4
  • Adi Layani
    • 4
  • Keren Slabodnik-Kaner
    • 3
    • 4
  • Erez N. Baruch
    • 2
    • 3
  • Guy Ben-Betzalel
    • 2
  • Elizabeth Grimm
    • 1
  • Raanan Berger
    • 5
    • 6
    • 7
  • Yehezkel Sidi
    • 4
  • Jacob Schachter
    • 2
    • 5
  • Ronnie Shapira-Frommer
    • 2
  • Dror Avni
    • 4
  • Gal Markel
    • 2
    • 3
    Email author
  • Raya Leibowitz-Amit
    • 5
    • 6
    • 7
    Email author
  1. 1.Departments of Melanoma Medical Oncology and Genomic MedicineThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Ella Lemelbaum Institute for Immuno-OncologySheba Medical Center-Tel HashomerRamat GanIsrael
  3. 3.Department of Clinical Microbiology and Immunology, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  4. 4.Lab of Molecular Cancer ResearchSheba Medical Center-Tel HashomerRamat GanIsrael
  5. 5.Department of Oncology, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  6. 6.Division of OncologySheba Medical Center-Tel HashomerRamat GanIsrael
  7. 7.Oncology Institute and Cancer Research Center, Sheba Medical Center-Tel HashomerRamat GanIsrael

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