IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v606y2022i7915d10.1038_s41586-022-04522-6.html
   My bibliography  Save this article

Androgen receptor activity in T cells limits checkpoint blockade efficacy

Author

Listed:
  • Xiangnan Guan

    (Oregon Health and Science University
    Oregon Health and Science University
    Genentech, Inc.)

  • Fanny Polesso

    (Oregon Health and Science University)

  • Chaojie Wang

    (Oregon Health and Science University
    Bristol Myers Squibb)

  • Archana Sehrawat

    (Oregon Health and Science University)

  • Reed M. Hawkins

    (Oregon Health and Science University)

  • Susan E. Murray

    (Oregon Health and Science University
    University of Portland)

  • George V. Thomas

    (Oregon Health and Science University
    Oregon Health and Science University)

  • Breanna Caruso

    (Oregon Health and Science University)

  • Reid F. Thompson

    (Oregon Health and Science University
    Oregon Health and Science University
    Oregon Health and Science University
    VA Portland Health Care System)

  • Mary A. Wood

    (VA Portland Health Care System)

  • Christina Hipfinger

    (Oregon Health and Science University)

  • Scott A. Hammond

    (AstraZeneca)

  • Julie N. Graff

    (Oregon Health and Science University
    VA Portland Health Care System)

  • Zheng Xia

    (Oregon Health and Science University
    Oregon Health and Science University
    Oregon Health and Science University)

  • Amy E. Moran

    (Oregon Health and Science University
    Oregon Health and Science University)

Abstract

Immune checkpoint blockade has revolutionized the field of oncology, inducing durable anti-tumour immunity in solid tumours. In patients with advanced prostate cancer, immunotherapy treatments have largely failed1–5. Androgen deprivation therapy is classically administered in these patients to inhibit tumour cell growth, and we postulated that this therapy also affects tumour-associated T cells. Here we demonstrate that androgen receptor (AR) blockade sensitizes tumour-bearing hosts to effective checkpoint blockade by directly enhancing CD8 T cell function. Inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. AR bound directly to Ifng and eviction of AR with a small molecule significantly increased cytokine production in CD8 T cells. Together, our findings establish that T cell intrinsic AR activity represses IFNγ expression and represents a novel mechanism of immunotherapy resistance.

Suggested Citation

  • Xiangnan Guan & Fanny Polesso & Chaojie Wang & Archana Sehrawat & Reed M. Hawkins & Susan E. Murray & George V. Thomas & Breanna Caruso & Reid F. Thompson & Mary A. Wood & Christina Hipfinger & Scott , 2022. "Androgen receptor activity in T cells limits checkpoint blockade efficacy," Nature, Nature, vol. 606(7915), pages 791-796, June.
  • Handle: RePEc:nat:nature:v:606:y:2022:i:7915:d:10.1038_s41586-022-04522-6
    DOI: 10.1038/s41586-022-04522-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-022-04522-6
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-022-04522-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Anastasia Samarkina & Markus Kirolos Youssef & Paola Ostano & Soumitra Ghosh & Min Ma & Beatrice Tassone & Tatiana Proust & Giovanna Chiorino & Mitchell P. Levesque & Sandro Goruppi & Gian Paolo Dotto, 2023. "Androgen receptor is a determinant of melanoma targeted drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Jean Lee & Leonid A. Yurkovetskiy & Derek Reiman & Lara Frommer & Zoe Strong & Anthony Chang & George J. Kahaly & Aly A. Khan & Alexander V. Chervonsky, 2024. "Androgens contribute to sex bias of autoimmunity in mice by T cell-intrinsic regulation of Ptpn22 phosphatase expression," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Mark C. Markowski & Mary-Ellen Taplin & Rahul Aggarwal & Laura A. Sena & Hao Wang & Hanfei Qi & Aliya Lalji & Victoria Sinibaldi & Michael A. Carducci & Channing J. Paller & Catherine H. Marshall & Ma, 2024. "Bipolar androgen therapy plus nivolumab for patients with metastatic castration-resistant prostate cancer: the COMBAT phase II trial," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Qian Liu & Emma Adhikari & Daniel K. Lester & Bin Fang & Joseph O. Johnson & Yijun Tian & Andrea T. Mockabee-Macias & Victoria Izumi & Kelly M. Guzman & Michael G. White & John M. Koomen & Jennifer A., 2024. "Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    5. Thanh Nguyen & Dhivya Sridaran & Surbhi Chouhan & Cody Weimholt & Audrey Wilson & Jingqin Luo & Tiandao Li & John Koomen & Bin Fang & Nagireddy Putluri & Arun Sreekumar & Felix Y. Feng & Kiran Mahajan, 2023. "Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:606:y:2022:i:7915:d:10.1038_s41586-022-04522-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.