Peripheral Blood IFN Responses to Toll-Like Receptor 1/2 Signaling Associate with Longer Survival in Men with Metastatic Prostate Cancer Treated with Sipuleucel-T

Mounting evidence links systemic innate immunity with cancer immune surveillance. In advanced metastatic castration-resistant prostate cancer (mCRPC), Black patients have been found to have increased inflammatory markers and longer survival after sipuleucel-T (sip-T) therapy, an FDA-approved, autologous cell therapy. We hypothesized these differences may be explained by previously reported ancestral differences in pattern recognition receptor signaling, which broadly governs innate inflammation to control adaptive immune cell activation, chemotaxis, and functionality. We discovered that peripheral blood mononuclear cell IFN-β responses to Toll-like receptor 1/2 (TLR1/2), a sensor of bacterial and gut microbiome constituents, associated with significantly longer survival after sip-T therapy in two separate cohorts of men with mCRPC (discovery cohort: n = 106, HR = 0.12; P = 0.019; validation cohort: n = 28, HR < 0.01; P = 0.047). Higher IFN-β induction after TLR1/2 stimulation was associated with lower HRs than biomarkers of vaccine potency and other prognostic factors in mCRPC. TLR1/2-dependent cytokine induction was stronger in Black individuals (1.2-fold higher for IFN-β; P = 0.04) but was associated with survival independently of race or numbers of vaccine-induced tumor antigen–specific T cells. IFN-β responses to TLR1/2 signaling correlated with increased numbers of IFN-γ producing T cells after broad, tumor antigen–independent stimulation. Thus, peripheral innate immunity differs by race, may predict survival after sip-T, and associates with peripheral T-cell functionality in men with mCRPC.

Michael C Brown,¹ Vincent M D'Anniballe,² David Boczkowski,³ Harini Kandadi,⁴ Nadeem Sheikh,⁴ William Kornahrens Jr,¹ Elisabeth I Heath,⁵ Archana Thakur,⁶ Wei Chen,⁵ Lawrence Lum,⁶ Frank C Cackowski,⁵ Julie Boerner,⁵ Michael D Gunn,² Andrew J Armstrong,^2,3,7 Smita K Nair^1,3,8

Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina.
Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
Department of Surgery, Duke University School of Medicine, Durham, North Carolina.
Dendreon Pharmaceuticals, LLC, Seattle, Washington.
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, Virginia.
Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, North Carolina.
Department of Pathology, Duke University School of Medicine, Durham, North Carolina.

Source: Brown MC., D'Anniballe VM., Boczkowskim D. et al. Peripheral Blood IFN Responses to Toll-Like Receptor 1/2 Signaling Associate with Longer Survival in Men with Metastatic Prostate Cancer Treated with Sipuleucel-T. Cancer Res Commun. 2024 Oct 1;4(10):2724-2733. doi: 10.1158/2767-9764.CRC-24-0439.

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