@article{d02be0a99955485182c9af27778b9d3b,
title = "Androgen receptor activity in T cells limits checkpoint blockade efficacy",
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.",
author = "Xiangnan Guan and Fanny Polesso and Chaojie Wang and Archana Sehrawat and Hawkins, {Reed M.} and Murray, {Susan E.} and Thomas, {George V.} and Breanna Caruso and Thompson, {Reid F.} and Wood, {Mary A.} and Christina Hipfinger and Hammond, {Scott A.} and Graff, {Julie N.} and Zheng Xia and Moran, {Amy E.}",
note = "Funding Information: R.F.T. and J.N.G. are employees of the US Government. The contents do not represent the views of the US Department of Veterans Affairs or the United States Government. S.A.H. is an employee of AstraZeneca. A.E.M. received research funding from AstraZeneca. Funding Information: We thank A. Adey and R. Searle for sharing expertise as we developed protocols for single-cell RNA-seq. We are grateful to the OHSU Department of Comparative Medicine for outstanding animal husbandry, the Massively Parallel Sequencing Shared Resource (MPSSR) for their support, and the Knight Cancer Institute Prostate Programs outstanding clinical research team. This work is funded in part by the Collins Medical Trust, OHSU Foundation, Prostate Cancer Foundation, Pacific Northwest Prostate Cancer SPORE NCI 5P50CA097186, NIH 1R37 CA263592-01 (to A.E.M.), M.J. Murdock Charitable Trust NS-201812034 (to S.E.M.), and a sponsored research agreement with MedImmune (to A.E.M.). This work is also supported by Medical Research Foundation at Oregon, NIH 5K01LM012877 and NIH 1R21HL145426 (to Z.X.). The resources of the Exacloud high performance computing environment developed jointly by OHSU and Intel and the technical support of the OHSU Advanced Computing Center are gratefully acknowledged. BioRender.com software was used for the creation of some figures. Funding Information: We thank A. Adey and R. Searle for sharing expertise as we developed protocols for single-cell RNA-seq. We are grateful to the OHSU Department of Comparative Medicine for outstanding animal husbandry, the Massively Parallel Sequencing Shared Resource (MPSSR) for their support, and the Knight Cancer Institute Prostate Programs outstanding clinical research team. This work is funded in part by the Collins Medical Trust, OHSU Foundation, Prostate Cancer Foundation, Pacific Northwest Prostate Cancer SPORE NCI 5P50CA097186, NIH 1R37 CA263592-01 (to A.E.M.), M.J. Murdock Charitable Trust NS-201812034 (to S.E.M.), and a sponsored research agreement with MedImmune (to A.E.M.). This work is also supported by Medical Research Foundation at Oregon, NIH 5K01LM012877 and NIH 1R21HL145426 (to Z.X.). The resources of the Exacloud high performance computing environment developed jointly by OHSU and Intel and the technical support of the OHSU Advanced Computing Center are gratefully acknowledged. BioRender.com software was used for the creation of some figures. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2022",
month = jun,
day = "23",
doi = "10.1038/s41586-022-04522-6",
language = "English (US)",
volume = "606",
pages = "791--796",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7915",
}