Evolution of myeloid-mediated mechanisms of immunotherapy resistance with prostate cancer progression

Patients with metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs), attributed in part to immunosuppressive myeloid cells within tumors. However, the heterogeneity of myeloid cells has made them challenging to target effectively, such as the clinical ineffectiveness of CSF1R blockade. By using single-cell profiling on patient biopsies, we find that a distinct population of tumor-associated macrophages expressing elevated SPP1 transcripts (SPP1hi-TAMs) becomes enriched with disease progression. In a syngeneic mouse model, an analogous macrophage population suppresses CD8+ T cell activity in vitro and promotes ICI resistance in vivo. Additionally, Spp1hi-TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signaling as a potential mechanism for SPP1hi-TAM-mediated immunotherapeutic resistance. Indeed, pharmacologic inhibition of adenosine receptors, A2AR, significantly reverses Spp1hi-TAM-mediated immune suppression on CD8+ T cells in vitro and enhances CRPC responsiveness to PD-1 blockade in vivo. Inhibiting A2AR results in a significant decrease in SPP1hi-TAM abundance in CRPC, suggesting targeting adenosine signaling could serve as a strategy to further augment the efficacy of ICIs by reshaping the myeloid landscape towards a less immunosuppressive state. Lastly, consistent with mouse data, inhibition of adenosine receptors using ciforadenant reverses resistance to atezolizumab in a subset of mCRPC patients, highlighting the therapeutic potential. Collectively, these findings demonstrate that SPP1hi-TAMs emerge as a key mediator of ICI resistance in mCRPC through adenosine signaling, emphasizing their significance as a therapeutic target