Evolution of myeloid-mediated immunotherapy resistance in prostate cancer

Aram Lyu, Zenghua Fan, Matthew Clark, Averey Lea, Diamond Luong, Ali Setayesh, Alec Starzinski, Rachel Wolters, Marcel Arias-Badia, Kate Allaire, Kai Wu, Vibha Gurunathan, Laura Valderrábano, Xiao X. Wei, Richard A. Miller, Eliezer M. Allen and Lawrence Fong ()
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Aram Lyu: University of California, San Francisco
Zenghua Fan: University of California, San Francisco
Matthew Clark: University of California, San Francisco
Averey Lea: University of California, San Francisco
Diamond Luong: University of California, San Francisco
Ali Setayesh: University of California, San Francisco
Alec Starzinski: University of California, San Francisco
Rachel Wolters: University of California, San Francisco
Marcel Arias-Badia: University of California, San Francisco
Kate Allaire: University of California, San Francisco
Kai Wu: University of California, San Francisco
Vibha Gurunathan: University of California, San Francisco
Laura Valderrábano: Dana-Farber Cancer Institute
Xiao X. Wei: Dana-Farber Cancer Institute
Richard A. Miller: Corvus Pharmaceuticals
Eliezer M. Allen: Parker Institute for Cancer Immunotherapy
Lawrence Fong: University of California, San Francisco

Nature, 2025, vol. 637, issue 8048, 1207-1217

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-024-08290-3

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