ScRNAseq of prostate cancer samples revealed an SPP1hi TAM population that correlated with progression and T cell exhaustion. In mice, Spp1hi TAMs were resistant to CSF1R blockade, suppressed T cell proliferation/polyfunctionality in vitro, and reduced the efficacy of ICB upon adoptive transfer. Spp1hi TAMs were associated with i.t. adenosine (ad) signaling pathways, and inhibition of ad signaling reduced TAM suppression of T cells in vitro. Ad receptor blockade alone or with ICB improved tumor control and T cell polyfunctionality in mice, and an analogous clinical regimen decreased PSA by 30+% in 6/24 patients, some of whom exhibited tumor regression.
Contributed by Morgan Janes
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 tumours(3,4). 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 (SPP1(hi)-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, Spp1(hi)-TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signalling as a potential mechanism for SPP1(hi)-TAM-mediated immunotherapeutic resistance. Indeed, pharmacological inhibition of adenosine A2A receptors (A2ARs) significantly reverses Spp1(hi)-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 SPP1(hi)-TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1(hi)-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.
Author Info: (1) Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. Parker Institute for Cancer Immunotherapy, San Francis
Author Info: (1) Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Immunotherapy Integrated Research Center, Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. (2) Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (3) Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (4) Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (5) Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (6) Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (7) Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (8) Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (9) Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (10) Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (11) Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (12) Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (13) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (15) Corvus Pharmaceuticals, Burlingame, CA, USA. (16) Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (17) Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. lawrence.fong@fredhutch.org. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. lawrence.fong@fredhutch.org. Immunotherapy Integrated Research Center, Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. lawrence.fong@fredhutch.org. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. lawrence.fong@fredhutch.org.
