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Nature, Dec 04 2024, | https://doi.org/10.1038/s41586-024-08290-3
Evolution of myeloid-mediated immunotherapy resistance in prostate cancer
Aram Lyu1,2,3,8, Zenghua Fan1,8, Matthew Clark1, Averey Lea1, Diamond Luong1, Ali Setayesh1, Alec Starzinski1, Rachel Wolters1, Marcel Arias-Badia1, Kate Allaire1, Kai Wu1, Vibha Gurunathan1, Laura Valderrábano4,5, Xiao X. Wei4, Richard A. Miller6, Eliezer M. Van Allen2,4,5 & Lawrence Fong1,2,3,7
1Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
2Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
3Immunotherapy Integrated Research Center, Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA.
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
5Broad Institute of MIT and Harvard, Cambridge, MA, USA.
6Corvus Pharmaceuticals, Burlingame, CA, USA.
7Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
8These authors contributed equally: Aram Lyu, Zenghua Fan.
Corresponding author
Correspondence to Lawrence Fong.
1Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
2Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
3Immunotherapy Integrated Research Center, Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA.
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
5Broad Institute of MIT and Harvard, Cambridge, MA, USA.
6Corvus Pharmaceuticals, Burlingame, CA, USA.
7Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
8These authors contributed equally: Aram Lyu, Zenghua Fan.
Corresponding author
Correspondence to Lawrence Fong.
Abstract
Patients with advanced metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs)1,2, partly because there are immunosuppressive myeloid cells in tumours3,4. However, the heterogeneity of myeloid cells has made them difficult to target, making blockade of the colony stimulating factor-1 receptor (CSF1R) clinically ineffective. Here we use single-cell profiling on patient biopsies across the disease continuum and find that a distinct population of tumour-associated macrophages with elevated levels of SPP1 transcripts (SPP1hi-TAMs) becomes enriched with the progression of prostate cancer to mCRPC. In syngeneic mouse modelling, an analogous macrophage population suppresses CD8+ T cell activity in vitro and promotes ICI resistance in vivo. Furthermore, Spp1hi-TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signalling as a potential mechanism for SPP1hi-TAM-mediated immunotherapeutic resistance. Indeed, pharmacological inhibition of adenosine A2A receptors (A2ARs) significantly reverses Spp1hi-TAM-mediated immunosuppression in CD8+ T cells in vitro and enhances CRPC responsiveness to programmed cell death protein 1 (PD-1) blockade in vivo. Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1hi-TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1hi-TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy.
논문정보
- Research article
- 2024년 12월 (BRIC 등록일 2024-12-06)
- 국외 연구진
- 생명과학 > 면역학
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