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Long-term Benefit of PD-L1 Blockade in Lung Cancer Associated with JAK3 Activation

Eliezer M Van Allen1, Hadrien G Golay2, Yan Liu2

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

Cancer Immunology Research
|May 28, 2015
PubMed

Insights

Activating JAK3 variants promote PD-L1 induction in lung cancer, driving response to immunotherapy. This discovery offers new insights into predicting patient response to immune checkpoint blockade therapy.

Area of Science:

  • Oncology
  • Immunology
  • Genetics

Background:

  • Immune checkpoint blockade, specifically targeting PD-1/PD-L1, offers durable responses in advanced metastatic cancers.
  • Predictors for response to PD-1 immune checkpoint blockade are not fully understood.
  • Lung adenocarcinoma is a significant cause of cancer mortality worldwide.

Purpose of the Study:

  • To investigate the genomic underpinnings of response to anti-PD-L1 therapy in a patient with refractory lung adenocarcinoma.
  • To identify mechanism-based predictors of immunotherapy response.

Main Methods:

  • Comprehensive genomic profiling of tumor and germline DNA.
  • Analysis of somatic and germline variants.
  • Assessment of PD-L1 expression in tumor cells and the immune microenvironment.

Main Results:

  • Discovery of activating somatic and germline amino acid variants in Janus Kinase 3 (JAK3).
  • Demonstration that these JAK3 variants promote PD-L1 induction in lung cancer cells.
  • Evidence that JAK3 variants contribute to PD-L1 upregulation within the tumor immune microenvironment.

Conclusions:

  • Genomic alterations in JAK3 can drive PD-L1 expression in lung cancer.
  • Deregulated cytokine receptor signal transduction may activate PD-L1 and the PD-1 immune checkpoint.
  • JAK3 variants represent a potential biomarker for predicting response to anti-PD-L1 immunotherapy in lung cancer.

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