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Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response

Author

Listed:
  • Meghana Pagadala

    (University of California San Diego)

  • Timothy J. Sears

    (University of California San Diego)

  • Victoria H. Wu

    (UCSD Moores Cancer Center)

  • Eva Pérez-Guijarro

    (National Cancer Institute, National Institutes of Health (NIH))

  • Hyo Kim

    (University of California San Diego)

  • Andrea Castro

    (University of California San Diego)

  • James V. Talwar

    (University of California San Diego)

  • Cristian Gonzalez-Colin

    (La Jolla Institute for Immunology)

  • Steven Cao

    (University of California San Diego)

  • Benjamin J. Schmiedel

    (La Jolla Institute for Immunology)

  • Shervin Goudarzi

    (Canyon Crest Academy)

  • Divya Kirani

    (University of California San Diego)

  • Jessica Au

    (University of California San Diego)

  • Tongwu Zhang

    (National Cancer Institute, National Institutes of Health (NIH))

  • Teresa Landi

    (National Cancer Institute, National Institutes of Health (NIH))

  • Rany M. Salem

    (University of California San Diego)

  • Gerald P. Morris

    (University of California San Diego)

  • Olivier Harismendy

    (University of California San Diego
    University of California San Diego School of Medicine)

  • Sandip Pravin Patel

    (UC San Diego Moores Cancer Center)

  • Ludmil B. Alexandrov

    (University of California San Diego
    University of California San Diego)

  • Jill P. Mesirov

    (University of California San Diego
    University of California San Diego)

  • Maurizio Zanetti

    (University of California San Diego
    University of California San Diego)

  • Chi-Ping Day

    (National Cancer Institute, National Institutes of Health (NIH))

  • Chun Chieh Fan

    (Laureate Institute for Brain Research
    University of California San Diego)

  • Wesley K. Thompson

    (University of California San Diego)

  • Glenn Merlino

    (National Cancer Institute, National Institutes of Health (NIH))

  • J. Silvio Gutkind

    (UCSD Moores Cancer Center)

  • Pandurangan Vijayanand

    (La Jolla Institute for Immunology)

  • Hannah Carter

    (University of California San Diego
    University of California San Diego)

Abstract

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.

Suggested Citation

  • Meghana Pagadala & Timothy J. Sears & Victoria H. Wu & Eva Pérez-Guijarro & Hyo Kim & Andrea Castro & James V. Talwar & Cristian Gonzalez-Colin & Steven Cao & Benjamin J. Schmiedel & Shervin Goudarzi , 2023. "Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38271-5
    DOI: 10.1038/s41467-023-38271-5
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