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Variations in genes involved in immune response checkpoints and association with outcomes in patients with resected colorectal liver metastases

The Pharmacogenomics Journal volume 15, pages 521–529 (2015)Cite this article

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Abstract

In patients with colorectal liver metastases (CLM), liver resection offers the possibility of cure and long-term survival. The liver is a highly immunogenic organ harboring ~80% of the body’s tissue macrophages. Emerging data demonstrate a critical role of the immune response for cancer treatment. We investigated variations within genes involved in immune response checkpoints and their association with outcomes in patients with CLM who underwent neoadjuvant chemotherapy including bevacizumab and liver resection. Single-nucleotide polymorphisms (SNPs) in nine genes (CCL2, CCR2, LAG3, NT5E, PDCD1, CD274, IDO1, CTLA4 and CD24) were analyzed in genomic DNA from 149 patients with resected bevacizumab-pretreated CLM by direct Sanger DNA sequencing, and correlated with response, recurrence-free survival (RFS), overall survival (OS), probability of cure and recurrence patterns. IDO1 (indoleamine 2, 3-dioxygenase) rs3739319 G>A and CD24 rs8734 G>A showed a significant difference in 3-year OS rates. In addition, IDO1 rs3739319 G>A was significantly associated with extrahepatic recurrence. Recursive partitioning analyses revealed that IDO1 rs3739319 G>A was the dominant SNP predicting RFS and OS. Our data suggest that variants within genes involved in immune response checkpoints are associated with outcomes in patients with resected CLM and might lead to improved treatment strategies modulating anti-tumor immune response by targeting novel immune checkpoints.

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Acknowledgements

SS is a recipient of an Erwin Schrödinger fellowship of the Austrian Science Fund (J 3501-B13). AS is a recipient of a Rio Hortega Research Grant from the Insituto de Salud Carlos III (CM11/00102). SS is supported by a postdoctoral fellowship from the German Cancer Aid (Mildred-Scheel Foundation). TG receives financial support by Roche, Merck-Serono, Sanofi-Aventis, Bayer and Amgen (all Vienna, Austria). H-JL receives financial support by the P30CA014089 NIH grant, and the Daniel Butler Research Fund.

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Authors and Affiliations

  1. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    S Stremitzer, Y Sunakawa, W Zhang, Y Ning, S Stintzing, A Sebio, S Yamauchi, S Matsusaka, R El-Khoueiry & H-J Lenz

  2. Department of Surgery, Medical University Vienna, Vienna, Austria

    S Stremitzer

  3. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    D Yang

  4. Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria

    J Stift & F Wrba

  5. Department of Surgery I, Rudolfstiftung Hospital, Vienna, Austria

    T Gruenberger

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TG is a member of the advisory boards of Roche, Merck-Serono and Sanofi-Aventis (all Vienna, Austria). H-JL is a member of the advisory board of Genentech (San Francisco, CA). The remaining authors declare no conflict of interest.

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Stremitzer, S., Sunakawa, Y., Zhang, W. et al. Variations in genes involved in immune response checkpoints and association with outcomes in patients with resected colorectal liver metastases. Pharmacogenomics J 15, 521–529 (2015). https://doi.org/10.1038/tpj.2015.14

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