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Tumor CDKN2A-Associated JAK2 Loss and Susceptibility to Immunotherapy Resistance

Susanne Horn1, Sonia Leonardelli1, Antje Sucker1

  • 1Department of Dermatology, University Hospital Essen, University Duisburg-Essen, and German Cancer Consortium partner site Essen/Düsseldorf, Essen, Germany (DKTK).

Journal of the National Cancer Institute
|June 20, 2018
PubMed

Insights

Acquired resistance to cancer immunotherapy, like anti-CTLA-4 and anti-PD-1, is linked to interferon-gamma (IFNγ) resistance. Loss of the tumor suppressor CDKN2A frequently leads to JAK2 deletion, increasing IFNγ resistance and immunotherapy failure.

Area of Science:

  • Oncology
  • Genetics
  • Immunology

Background:

  • Checkpoint blockade therapies (anti-CTLA-4, anti-PD-1) show poor responses in some melanoma patients.
  • Acquired interferon-gamma (IFNγ) resistance in tumor cells contributes to treatment failure.
  • IFNγ resistance is often due to loss of the JAK2 gene in the IFNγ signaling pathway.

Purpose of the Study:

  • To investigate the relationship between chromosomal losses, specifically CDKN2A, and the development of IFNγ resistance in melanoma and other cancers.
  • To determine if CDKN2A deletions predict JAK2 deficiency and subsequent immunotherapy resistance.

Main Methods:

  • Analysis of 46 melanoma cell lines using next-generation targeted sequencing and SNP arrays.
  • Examination of The Cancer Genome Atlas (TCGA) genomic data for multiple cancer types (melanoma, lung, bladder, breast, colorectal).
  • Statistical analysis to assess the association between CDKN2A loss and JAK2 deletion.

Main Results:

  • Frequent chromosomal losses of the tumor suppressor CDKN2A enhance susceptibility to IFNγ resistance through concomitant JAK2 gene deletion (OR = 223.17, P = 7.6×10-46).
  • Tumors with JAK2 mutations or homozygous deletions show allelic losses affecting both CDKN2A and JAK2.
  • This association was observed across multiple cancer types, not just melanoma.

Conclusions:

  • Patients with tumor chromosomal CDKN2A losses are at higher risk of developing resistance to immune checkpoint blocking therapies.
  • Screening for JAK2 deficiency in patients with CDKN2A loss is recommended before and during immunotherapy.
  • Understanding these genetic alterations can guide personalized treatment strategies for immunotherapy.

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