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

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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.

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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

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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.

Author information

Author notes

  1. Gal Markel and Raya Leibowitz-Amit are equal corresponding authors.

  2. Jason Roszik and Ettai Markovits contributed equally to this work.

Authors and Affiliations

  1. Departments of Melanoma Medical Oncology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Jason Roszik & Elizabeth Grimm

  2. Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel

    Ettai Markovits, Erez N. Baruch, Guy Ben-Betzalel, Jacob Schachter, Ronnie Shapira-Frommer & Gal Markel

  3. Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel

    Ettai Markovits, Keren Slabodnik-Kaner, Erez N. Baruch & Gal Markel

  4. Lab of Molecular Cancer Research, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel

    Paula Dobosz, Adi Layani, Keren Slabodnik-Kaner, Yehezkel Sidi & Dror Avni

  5. Department of Oncology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel

    Raanan Berger, Jacob Schachter & Raya Leibowitz-Amit

  6. Division of Oncology, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel

    Raanan Berger & Raya Leibowitz-Amit

  7. Oncology Institute and Cancer Research Center, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel

    Raanan Berger & Raya Leibowitz-Amit

Authors
  1. Jason Roszik
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  2. Ettai Markovits
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  3. Paula Dobosz
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  7. Guy Ben-Betzalel
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  8. Elizabeth Grimm
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  14. Gal Markel
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  15. Raya Leibowitz-Amit
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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.

Corresponding authors

Correspondence to Gal Markel or Raya Leibowitz-Amit.

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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).

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

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Roszik, J., Markovits, E., Dobosz, P. et al. TNFSF4 (OX40L) expression and survival in locally advanced and metastatic melanoma. Cancer Immunol Immunother 68, 1493–1500 (2019). https://doi.org/10.1007/s00262-019-02382-0

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  • DOI: https://doi.org/10.1007/s00262-019-02382-0

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