Type I Interferon priming in Macrophages is associated with poor responses in Patients with Advanced Prostate Cancer

Introduction/Rationale: Prostate cancer patients acquire resistance to standard-of-care strategies resulting in 350,000 yearly deaths. As acquired resistance is mediated by increased androgen receptor (AR) expression, “Bipolar Androgen” therapy (BAT) is being developed to cycle serum testosterone from supraphysiological to near-castrate levels, maximizing toxicity to high and low AR-expressing cells respectively. BAT is a clinically effective and safe approach that improves quality of life, produces biochemical and objective responses, and re-sensitizes tumors to AR inhibitors. We previously demonstrated that despite its conception as a “targeted” therapy, BAT’s effects on the immune system appear critical for success.

Methods: We examined immune cells from tumor biopsies and peripheral blood mononuclear cells (PBMCs) before and after BAT, using spectral flow cytometry, single cell RNA sequencing and spatial transcriptomics.

Results: We found that macrophages in tumors of non-responding patients have increased Type I IFN gene expression, compared to responding patients. As macrophages in tumors arise from circulating monocytes, we examined how monocyte tumor engraftment was impacted by BAT. Intriguingly, classical monocytes display enhanced expression of Type I IFN response genes only in patients with poor responses, mimicking what we observed in tumors. Moreover, we discovered a subset of Type I IFN primed monocytes that are increased in frequency in these patients and demonstrated their altered response to IFN alpha and ability to generate macrophages with an altered phenotype.

Conclusion: BAT reprograms circulating monocytes, conferring a Type I IFN signature that is mirrored by macrophages in tumors from patients with poor therapeutic response. Type I IFN has been associated with resistance to other cancer therapies and could play an important role in limiting immune control of prostate cancer following BAT. Critically, BAT reprograms tumor immunity and our results provide an attractive target to improve this therapy.