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Evolution of myeloid-mediated immunotherapy resistance in prostate cancer

ABSTRACT: Patients with advanced metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs), partly because there are immunosuppressive myeloid cells in tumours. 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE274229 | GEO | 2024/12/04

REPOSITORIES: GEO

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Project description:Purpose: PTEN loss-of-function occurs in ~50% of metastatic, castrate-resistant prostate cancer (mCRPC) patients, and associated with poor prognosis and responsiveness to standard-of-care therapies and immune checkpoint inhibitors. While PTEN loss-of-function hyperactivates PI3K signaling, combinatorial PI3K/AKT pathway and androgen deprivation therapy (ADT) has demonstrated limited anti-cancer efficacy in clinical trials. Here, we aimed to elucidate mechanism(s) of resistance to ADT/PI3K-AKT axis blockade, and to develop rational combinatorial strategies to effectively treat this molecular subset of mCRPC. Experimental design: Prostate-specific PTEN/p53-deficient genetically engineered mice (GEM) with established 150-200 mm3 tumors, as assessed by ultrasound, were treated with either ADT (degarelix), PI3K inhibitor (copanlisib), or anti-PD-1 antibody (aPD-1), as single agents or their combinations, and tumors were monitored by MRI and harvested for immune, transcriptomic and proteomic profiling, or ex vivo co-culture studies. Single-cell RNAseq on human mCRPC samples was performed using 10X Genomics platform. Results: Co-clinical trials in PTEN/p53-deficient GEM revealed that recruitment of PD-1-expressing tumor-associated macrophages (TAM) thwarts ADT/PI3Ki combination-induced tumor control. The addition of aPD-1 to ADT/PI3Ki combination led to TAM-dependent ~3-fold increase in anti-cancer responses. Mechanistically, decreased lactate production from PI3Ki-treated tumor cells suppressed histone lactylation within TAM, resulting in their anti-cancer phagocytic activation, which was augmented by ADT/aPD-1 treatment and abrogated by feedback activation of Wnt/β-catenin pathway. Single-cell RNA-sequencing analysis in mCRPC patient biopsy samples revealed a direct correlation between high glycolytic activity and TAM phagocytosis suppression. Conclusions: Immunometabolic strategies that reverse lactate and PD-1-mediated TAM immunosuppression, in combination with ADT, warrant further investigation in PTEN-deficient mCRPC patients.

Project description:High-grade gliomas, the most common and aggressive primary brain tumors, are characterized by a complex and multifaceted tumor microenvironment (TME). Among the non-malignant cells of the glioma TME, tumor-associated microglia and macrophages (TAMs) constitute the major compartment. In patients, a greater abundance of TAMs is associated with high-grade and more aggressive disease. In a range of glioma mouse models, we have observed specific alterations in TAM dynamics and functions during tumor development and following different therapeutic interventions, including irradiation. The underlying TAM abundance may also modulate the subsequent response to TAM-targeted therapy, including the anti-CSF1R inhibitor BLZ945, which results in a pronounced tumor regression in different preclinical models of brain cancers, as our lab has recently shown. These observations indicate that it is crucial to evaluate TAM abundance and dynamics in gliomas. Current techniques to quantify TAMs in patients rely mainly on histological staining of tumor biopsies. While informative, these techniques require an invasive procedure to harvest the tissue sample and typically only result in a snapshot of a small region at a single point in time. Fluorine isotope 19 MRI (19F MRI) has been shown to be a powerful tool to non-invasively and longitudinally monitor myeloid cells in other pathological conditions by injecting perfluorocarbon-containing nanoparticles (PFC-NP). In this study, we demonstrated the feasibility and power of 19F MRI in preclinical glioma models and brain metastasis models and showed that the major cellular source of 19F signal consists of TAMs. Moreover, PFC-NP accumulation occurred predominantly in proximity to dysmorphic vessels, thereby enabling the identification of a TAM subpopulation with a specific oxidative metabolism. We also evaluated this imaging modality in the context of irradiation (IR) treatment and found that the 19F signal enables the tracking of TAM dynamics over time following IR. Moreover, multispectral 19F MRI with two different PFC-NP allowed us to identify spatially- and temporally-distinct TAM niches in IR-recurrent tumors. Together, we have been able to image TAMs non-invasively and longitudinally with a powerful integrated cellular, spatial and temporal resolution, while revealing new biological insights into the many functions of TAMs, including in disease recurrence.

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Evolution of myeloid-mediated immunotherapy resistance in prostate cancer

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